REVIEW ARTICLE
Year : 2018 | Volume
: 1 | Issue : 3 | Page : 63--71
The role of integrins in acute leukemias and potential as targets for therapy
Amal A Elsharif, Laurence H Patterson, Steven D Shnyder, Helen M Sheldrake
Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, United Kingdom
Correspondence Address:
Dr. Helen M Sheldrake
Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP
United Kingdom
Abstract
The interaction between the bone marrow microenvironment and leukemia cells enhances cell adhesion-mediated signals that can promote malignant hematopoietic cell survival and change normal hematopoiesis. Integrins, on the surface of leukemia cells, are involved in this interaction and mediate cell adhesion to integrin receptors of other cells and the extracellular matrix. Studies show that inhibition of several integrins affects leukemia cell migration or survival as well as sensitivity to chemotherapy. This review focuses on the expression and role of key arginine–glycine–aspartate acid (RGD)-binding (αvβ3, α5β1, αIIbβ3) and non-RGD-binding (α2β1, α4β1, α6β1, and αLβ2) integrins on leukemia cells and in the leukemia microenvironment and their potential targeting in leukemia treatment.
How to cite this article:
Elsharif AA, Patterson LH, Shnyder SD, Sheldrake HM. The role of integrins in acute leukemias and potential as targets for therapy.Tumor Microenviron 2018;1:63-71
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How to cite this URL:
Elsharif AA, Patterson LH, Shnyder SD, Sheldrake HM. The role of integrins in acute leukemias and potential as targets for therapy. Tumor Microenviron [serial online] 2018 [cited 2023 Mar 25 ];1:63-71
Available from: http://www.TMEResearch.org/text.asp?2018/1/3/63/266936 |
Full Text
Introduction
The bone marrow microenvironment controls function, differentiation, and survival of both normal hematopoietic and leukemia cells.[1],[2] Both the vascular and osteoblastic niches are crucial for leukemia cell proliferation, differentiation, and survival.[3],[4]
Leukemia cells share features of specific differentiation and self-renewal with multipotent hematopoietic stem cells. Some of the molecular pathways mediating interactions between leukemia cells and the bone marrow microenvironment are identical to those of hematopoietic stem cells, including integrin signaling [5] and CXCR4/CXCL12 signaling, which participates in homing of hematopoietic stem cells and leukemia cells into bone marrow and activates β1 and β3 integrins.[4] However, leukemia cells differ from hematopoietic cells by impairment of regulatory signaling mechanisms governing survival, proliferation, and invasive and dissemination capabilities.[6],[7],[8]
Interaction between the bone marrow microenvironment and leukemia cells represents a significant cause of patient relapse. Components of the microenvironment such as integrins participate in engrafting leukemia cells into the microenvironment niches. These lead to cell survival, progression, and chemoresistance; after treatment is completed, late relapse occurs through inhibition of chemotherapy-induced programmed cell death in leukemia cells.[9],[10],[11]
The permissive microenvironment generated by stromal cells, growth factors, and cytokines is also involved in the initiation of leukemia, its development, and dissemination, whereas leukemia cells impact on stromal cells through secreted factors and cell–cell interactions.[12] Stromal ligands such as fibronectin (Fn) interact with leukemia blast integrins,[13],[14] and this adhesive interaction is required for leukemia blast proliferation and survival. Stromal cells also regulate migration and leukemia blast cell growth. The influence of stromal cells on leukemia blasts seems similar to normal physiological cell–cell adhesion through adhesive receptors such as integrins in hematopoietic progenitors. In leukemic blasts and stromal cells, reciprocal activation of the integrin-linked kinase (ILK/Akt) pathway is important for adhesion-driven acute myeloid leukemia (AML) blast survival.[12] The integrins are, thus, significant cell adhesion molecules,[15],[16] critical in human acute leukemia survival.
Integrins
Integrins are family I transmembrane heterodimeric glycoprotein receptors which mediate cell–cell, cell–extracellular matrix (ECM), and cell–pathogen interactions, associating the extracellular and intracellular environments. They transfer signals bidirectionally across the plasma membrane and regulate multiple biological functions, including cell differentiation, cell migration, and wound healing.[17],[18]
A characteristic of integrins is the individual family members' ability to bind multiple ligands. The major extracellular ligands of integrins include ECM proteins such as bone matrix proteins, Fn, collagens, fibrinogen (Fg), thrombospondins, laminins, von Willebrand factor, vitronectin (Vn), bone sialoprotein, osteopontin (Opn), and nephronectin, reflecting the primary role of integrins in the adhesion of cells to extracellular matrices.[19]
Structurally, integrins are noncovalent heterodimers containing an α and a β glycoprotein subunit.[16],[20],[21] Eight β and 18 α subunits combine to form 24 human αβ integrin dimers.[21],[22],[23],[24] These 24 recognized integrin heterodimers are subdivided into arginine–glycine–aspartate acid (RGD)-binding, leukocyte adhesion integrins, collagen-binding, and laminin-binding integrins.[25]
The eight RGD-recognizing integrins [Table 1] recognize the common RGD tripeptide sequence at a binding site formed at the α and β subunit headpiece junction.[19] The non-RGD-binding integrins, including α2β1, α4β1, and α6β1 [Table 2], recognize a range of different sequences in their ligands. Many non-RGD-binding integrins bind their ligands using an I-domain located entirely in the α subunit.[51] Leukocyte adhesion integrins are non-RGD-binding integrins and contain the β2 or α4 subunits.[43]{Table 1}{Table 2}
Integrins have proved popular targets for disease-modifying therapies, and many analyses have demonstrated their roles in cancer progression,[52],[53],[54],[55],[56] including leukemia.[57] Here, we review the most significant integrins involved in microenvironment interactions in acute leukemia.
Integrins in Acute Leukemia
Arginine–glycine–aspartate acid-binding integrins
αvβ3 Integrin
Interaction of the bone marrow microenvironment with immature hematopoietic cells is significant in several processes, including differentiation and proliferation of hematopoietic progenitor cells, mobilization of progenitor cells, and persistence of residual disease in leukemia.[58]
Adhesion within the marrow microenvironment leads to chemotherapy resistance in AML and other hematologic malignancies by interfering with apoptosis or activating survival pathways.[59] Expression of β3 is crucial for Opn-enhanced chemotherapy insensitivity in AML cells.[60] Both β3 and the related β5 subunit are linked to relapse and overall prognosis in T-cell acute lymphocytic leukemia (T-ALL); nonspecific inhibition of these integrins with an RGD peptide increased apoptosis in vitro.[61]
Lymphoid tumor cells (CEM T-cell lymphoblastic leukemia, Burkitt's lymphoma, and U266 multiple myeloma) have been shown to interact with ECM components such as Vn and Fn via αvβ3. Interaction with Vn and Fn allows cells to attach to the substratum and increases proliferation and protease secretion. Binding to αvβ3 promotes formation of activated Src/FAK complexes and activation of ERK-2. Engagement of αvβ3 also promotes human lymphoid tumor dissemination by modulating cell adhesion, proliferation, and interacting with ECM components.[62] In AML, αvβ3 is upregulated in dormant cells and increases their adhesion to Vn;[63] therefore, αvβ3 inhibition is a candidate therapeutic strategy for total eradication of leukemia cells.
Both β3 and αv are required for mixed-lineage leukemia (MLL)-AF9 cells to maintain the leukemia phenotype.[63] MLL-AF9 cells interact with the bone marrow microenvironment, most probably in the endosteal region.[64] This interaction is important for cell survival and affects lineage fate.[65] Expression of β3 and αv has also been confirmed on primary human AML cells with and without MLL rearrangement.[66]
The ITGB3 gene has been identified as essential in human and murine leukemia cells in vivo.[60],[67] β3 knockdown impaired homing of primary leukemia cells, induced differentiation of myeloid cells via spleen tyrosine kinase (SYK), and downregulated leukemia stem cell transcriptional programs. In contrast, loss of β3 in normal hematopoietic cells did not impair progenitor or stem cell differentiation or function in primary transplants. In this mouse model, β3 was not necessary for normal hematopoiesis, but was essential for leukemogenesis, demonstrating the importance of the integrin β3 signaling pathway as a target in AML. Therefore, inhibiting integrin β3–SYK signaling might provide a strategy to reduce leukemia growth without normal tissue toxicity. These data indicate a significant role for β3 in both leukemic cells themselves and their interaction with stromal cells.[67]
Increased expression and activation of β3 in human AML cells (Mll-Ell+) can result from increased activation of HoxA9 and HoxA10, which bind the ITGB3 promoter.[66],[68] High expression of Hox proteins in AML cells is also associated with Syk activation. Inhibition of the fibroblast growth factor receptor resulted in decreased β3 expression, cell adhesion, and proliferation through reducing the expression of HoxA9 and HoxA10.[68] This suggests that high β3 expression may be used as a biomarker identifying patient eligibility for some targeted therapies, but also that caution is required when combining targeted therapeutics with integrin-targeted agents as they may change the expression of the integrin target.
αvβ3 Signaling and chemosensitivity
Sorafenib is a multikinase inhibitor under investigation (off-label use) for the treatment of AML. However, αvβ3 signaling in the bone marrow microenvironment leads to sorafenib insensitivity, affecting AML prognosis particularly in Fms-like tyrosine kinase-3 internal tandem duplication-mutated AML.[60] Mechanistically, the microenvironment's influence on sorafenib sensitivity results from αvβ3 enhancing β-catenin activation through phosphatidylinositol 3-kinase (PI3K)/glycogen synthase kinase-3 (GSK3) β-catenin signaling. αvβ3 also shows downstream crosstalk with intracellular signaling pathways inducing SYK and affects the regulation of transcription, cell homing, and induction of differentiation of leukemia cells.[57],[69]
Targeting the αvβ3/Opn interaction in leukemia cells leads to enhanced chemosensitivity in AML.[70] Blocking αvβ3 using c(RGDfK) made AML cells more sensitive to cytarabine through inhibiting their ability to attach to Opn and migrate in 3D microenvironments. Combination of specific αvβ3 inhibition with cell signaling pathway inhibitors (inhibition of Syk) is another potential strategy for inhibiting AML-supporting signaling pathways.[57],[61]
Taken together, these studies suggest that αvβ3 integrin inhibitors combined with current chemotherapies or cell signaling inhibitors may be efficient in reducing chemoresistance and patient relapse.
αllbβ3 Integrin
αIIbβ3 is the main membrane protein [33] and primary adhesion receptor of blood platelets.[71] Fg has six potential binding sites for αIIbβ3, containing RGD and KQAGDV sequences, both recognized by the RGD-binding site. Platelets binding to Fg leads to crosslinking and platelet aggregation as a central response to thrombosis and hemostasis triggers.[72]
αIIbβ3 has also been detected on solid and hematologic tumor cells.[73],[74],[75] The β3 integrin expression level on AML cells is comparable with that on endothelial cells associated with solid tumors.[57],[76] αIIbβ3 has high expression in acute megakaryoblastic AML, providing a diagnostic characteristic.[77] αIIb, β1, β3, and α5 are all critical for attaching erythroleukemia cells to Fn.[78]
Plasma Fg levels at the time of diagnosis have a prognostic association with worse progression-free and overall survival in AML patients, but not with response to initial treatment.[79] Both solid-phase and soluble Fg promote Syk signaling in human megakaryoblastic cell lines by binding to αIIbβ3, suggesting that αIIbβ3-Fg interactions may promote treatment resistance and relapse. Thrombopoietin also enhances the adhesion of leukemic cells to Fg and Fn through activation of αIIbβ3 via PI3K signaling.[80] The effect is only seen with αIIbβ3; adhesion is not reversed by inhibiting αvβ3, suggesting a role for dual β3 inhibition in reversing the effects of leukemia-ECM interactions.
K562 leukemia cells undergo megakaryocytic differentiation in response to phorbol 12-myristate 13-acetate (PMA). This results in the expression of αIIb and β3, which are often utilized as differentiation markers of the megakaryocyte cell lineage.[81] PMA-stimulated K562 cell adhesion promoted by integrin agonists is partially inhibited by selective αIIbβ3 and α5β1 antagonists, demonstrating that both α5β1 and αIIbβ3 integrins mediate K562 cell adhesion.[82] Therefore, combining αIIbβ3 and α5β1 inhibition may provide a potential clinical strategy in antileukemia drug development.
α5β1 Integrin
α5β1 is a specific receptor for Fn. Both α5β1 and Fn play a significant role in the development of the vascular system during embryogenesis.[83],[84] α5β1 integrin ligation stimulates cell growth and migration during Akt and MAPK activation-mediated signaling pathways.[74] Expression of α5β1 is upregulated in endothelial cells within new blood vessels and also on the surface of several tumors such as breast, ovarian, and colorectal carcinoma.[85]
α5β1 is expressed in T-ALL, where it can mediate interactions with ECM proteins during the transmigration process.[86] Aberrant glycosylation of α5β1 promotes adhesion, downstream signaling, and invasion of ALL cells.[87] Binding to Fn triggers intracellular signaling, leading to the expression of pro-MMP-9 in the K562 myeloid leukemia model, promoting migration. Use of a blocking anti-α5 mAb represses the activity of pro-MMP-9.[88] Binding to CD154 also triggers α5β1-mediated survival signaling, and the CD154/α5β1 interaction is proposed as a novel molecular target, which is pivotal in the progression of T-cell-derived cancers.[89]
Integrins and tyrosine kinases contribute to mediating signals for cell survival and suppressing programmed cell death in ALL bearing the Philadelphia chromosome (Ph + leukemia). An α5 inhibitory antibody prevented adhesion of Ph + leukemia cells to Fn and acted synergistically with the BCR-ABL fusion protein inhibitor imatinib to enhance apoptosis. In immunodeficient mice, α5 inhibition delayed and impaired the engraftment of Ph + leukemia cells.[90]
Interactions with Fn controlling chemosensitivity may be mediated by both α5β1 and α4β1.[91],[92] α5β1 can specifically trigger activation of GSK3β via PP2A, thus promoting cell survival under adverse conditions.[91] α4β1 prosurvival signaling involves PI-3K/AKT/Bcl-2.[91],[92] These complementary prosurvival pathways again suggest that dual/multi-integrin inhibitors may be required to overcome receptor redundancy and/or crosstalk triggering resistance to intrinsic and extrinsic apoptotic pathways.
Non-arginine–glycine–aspartate acid-binding integrins
α2β1 Integrin
α2β1 (very late antigen 2, CD49b) on endothelial, epithelial, and hematopoietic cells serves as a receptor for collagens and laminins. α2β1 plays a significant role in homeostasis and platelet function [93] and is also involved in cell survival, migration, invasion, and angiogenesis.[94] Aberrations in α2β1 expression have been shown in a range of different cancers [94],[95] and in skeletal metastases leading to α2β1's identification as a possible cancer biomarker.[96] Recently, high α2β1 expression was established as an independent prognostic factor in AML patients, and hence, it may serve specifically as a biomarker of treatment response and relapse.[94]
Binding of α2β1 to collagen blocked doxorubicin-induced programmed cell death of T-ALL by inactivating c-Jun N-terminal kinase (JNK).[97] This effect is mediated by the MAPK/ERK survival pathway, which is activated by a number of integrins, although binding Fn via α4β1 did not protect cells in this model. These data suggest disease-specific tumor-microenvironment interactions control response.[97] In a 3D model, interaction of T-ALL cell lines and primary patient-derived cells with Matrigel also protected cells from the effects of doxorubicin, an important chemotherapeutic against T-ALL, by activation of the ABCC1 transporter and PYK2 signaling. A xenograft model showed that β1 inhibition sensitized T-ALL to doxorubicin and increased survival.[98] While these results clearly support the use of β1 inhibitors in leukemia treatment, more research is required to identify the α subunit(s) involved.
The full role of α2β1 in acute myeloid and lymphoblastic leukemias is still incompletely understood. However, recent studies suggest that it may have similar consequences to β3 integrin-mediated adhesion, so inhibitors may find a place in combination therapies alongside other integrins.
α4β1 Integrin
α4β1 (very late antigen 4, CD49d/CD29) recognizes multiple sequences in Opn, Fn, and vascular cell adhesion molecule-1 (VCAM-1), including RGD and DXP sequences.[99],[100] α4β1 is involved in the regulation of the inflammatory response by mediating adhesion to cellular VCAM-1 and Fn. It also contributes to the mobilization and retention of immature progenitors in the bone marrow, and antigen-presenting cell–lymphocyte interactions.[101]
Studies of the relationship between α4β1 expression and patient prognosis have shown contradictory results, with larger-scale clinical studies suggesting high expression is associated with favorable outcomes.[102] However, adhesion within the bone marrow microenvironment leads to chemotherapy resistance in AML by interfering with apoptosis or activating cell survival pathways.[59],[92] Therefore, inhibition of cell adhesion can reverse chemotherapy resistance. For example, in xenotransplant models, the anti-α4-integrin antibody natalizumab completely eradicated B-cell ALL.[103] A small-molecule α4β1 inhibitor (TBC3486) was able to prolong survival although it did not fully eradicate leukemia cells,[104] reiterating the difficulties in dosing small molecules with relatively short half-lives compared to mAbs to achieve effective target coverage which have also been seen with other small-molecule integrin antagonists, notably cilengitide.[105] Natalizumab is already used in in the treatment of Crohn's disease and multiple sclerosis and has been subjected to long-term safety assessment; its severe side effect of progressive multifocal leukoencephalopathy has encouraged the development of other α4-targeting agents as antileukemics.[59],[106]
ATL1102, an antisense oligonucleotide targeting α4, effectively downregulates the α4 and β1 subunits and upregulates CXCR4 in vitro, but had no effect on α4 expression or survival in vivo pre-B-cell ALL cells in mouse xenografts.[107] Further development of ATL1102 is needed to improve its in vivo cellular delivery. Other strategies for reducing integrin expression have also been investigated preclinically. For example, methylseleninic acid reduces β1 expression, thereby detaching leukemia cells from Fn.[108]
An oral α4 antagonist, AVA-4746, prolongs survival when used in combination with conventional chemotherapy in a mouse xenograft model of primary pre-B ALL, and investigations on its use to eradicate minimal residual disease in ALL are ongoing.[109] Because AVA-4746 has been proven safe in clinical trials for the mobilization of hematopoietic stem cells, it is a promising potential candidate.
Overall, preclinical studies support the possibility of repurposing anti-α4 agents as a new strategy for overcoming chemotherapy resistance in acute leukemia.
α6β1 Integrin
α6β1 is a major laminin receptor and a significant mediator in the growth of tumor blood vessels,[110] as well as platelet adhesion and activation in response to laminins.[49] Expression of α6β1 is common in ALL which permits cells to utilize migratory neural pathways from bone marrow to invade the central nervous system.[111],[112]
α6 can also partner with the β4 subunit. Significantly elevated expression of α6 is observed in AML with high expression of the ecotropic viral integration site 1 (EVI1) oncogene, in addition to the expression of β3 and β4. The presence of α6β1 was not determined. EVI1 (high) AML cells have a high ability of adhesion to laminin via α6β4 that leads to resistance to chemotherapy.[113] β3 inhibition did not affect the adhesion of these cells to Matrigel, indicating that targeting α6-containing integrins may be required in addition to targeting β3 integrins to effectively reverse chemoresistance in some types of leukemias.
αLβ2 Integrin
αLβ2 (LFA-1, CD11a/CD18) is a leukocyte-specific integrin, which binds intracellular cell adhesion molecule-1. This interaction is essential for firm adhesion of leukocytes to endothelial cells, and its relevance to cancer has been previously reviewed.[114],[115] In T-ALL, αLβ2 is constitutively activated, promoting extravasation.[116]
High αLβ2 expression is associated with brain infiltration [117] and relapse in both ALL [117],[118] and AML.[118] However, loss of αL is a specific marker of acute megakaryoblastic leukemia in pediatric patients.[119] Targeting αLβ2 has been proposed as a method of targeting drugs to leukocytes.[115] Leukotoxin, a protein derived from Aggregatibacter actinomycetemcomitans, has been shown to bind specifically to activated αLβ2 and induce cell death, acting synergistically with standard chemotherapy agents.[120],[121] Leukotoxin is currently in preclinical development for indications including leukemia and lymphoma. However, targeting αL has demonstrated the same issues as targeting α4; the antibody efalizumab was withdrawn from the market due to the risk of progressive multifocal leukoencephalopathy.
Integrins in the CXCR4 Pathway
The CXCR4/CXCL12 chemokine axis regulates the interaction of malignant cells with ECM proteins such as Fn and laminin, which share in metastatic dissemination.[122],[123] CXCR4/CXCL12 signaling enhances expression of integrin subunits including β3 and β1 subunits and leads to activation of ILK and FAK, upregulation of JNK, ERK1/2, and phosphorylation of p38. Consequently, chemokine receptor crosstalk with integrins may be a major part in mediating cell adhesion.[124],[125] Both the β3 and β1 integrin subunits in leukemia are involved in homing and attachment of acute leukemia cells to the bone,[59],[67] and both participate in the common CXCR4/CXCL12 axis.[102],[126]
Accumulating data across a range of cancer types propose that CXCR4 engagement by CXCL12 cooperates with integrin signaling in mediating chemoresistance and induces integrin-mediated adhesion.[123] In acute pediatric leukemias, CXCR4/CXCL12 and β1 are involved in a multiprotein complex mediating chemoresistance.[127] A combination of α4β1 and CXCR4 expression has been proposed as a prognostic biomarker in adult AML.[102] Targeting of β3 and β1 with CXCR4 in leukemia cells is a potential strategy to improve leukemia treatment in the future.
Conclusion
Cancer cell–microenvironment interactions are vital for growth and survival of leukemia cells. Many studies show that multiple integrins are involved in leukemia/microenvironment interaction, affecting both drug sensitivity and cell growth.[64] Given the importance of αvβ3, α5β1, αIIbβ3, α2β1, α4β1, α6β1, and αLβ2 integrins in the progression of a number of hematological malignancies [Table 3], there is significant therapeutic potential for the application of integrin antagonists. All of the studies reviewed above using integrin inhibition in leukemia models have suggested that it is a promising strategy for leukemia treatment. αvβ3 seems to be essential for disease progression and chemosensitivity in leukemia in some specific subsets of AML patients. Interaction of leukemia cell α5β1 and α4β1 with stromal Fn is involved in AML minimal residual disease and chemoinsensitivity. Many intracellular signaling and transcriptional regulators are also involved in integrin functions in AML.{Table 3}
Several questions and challenges remain to be addressed to bring integrin antagonists successfully to the clinic. Redundancy and overlapping functions of multiple integrins requires careful research to identify the optimum combination of integrins to be targeted for effective treatment of each leukemia type. αIIb and other integrins (β1, β3, and α5) are all significant for adhesion of erythroleukemia cells to Fn. Therefore, a combination of αIIbβ3-targeted therapies with other molecular targeted therapies should be considered in future leukemia treatment. Future studies have to clarify whether targeting β3 alongside β1 and CXCR4/CXCL12 signaling axis will be useful in all acute leukemias or the only specific types. Lessons learned in the development of integrin antagonists for other disease indications will need to be applied, for example, serious adverse effects observed with α4 and αL antagonists in autoimmune diseases suggest that caution is needed in developing or repurposing leukocyte integrin antagonists in leukemias. Over the past 40 years, understanding of integrins has developed from simple cell surface adhesion molecules to receptors with a complex range of intracellular and extracellular functions. Application of recent research on the features of ligands controlling full antagonism and partial agonism, and improved understanding of the roles of under-researched integrins, will allow new therapeutics to be developed for safe and effective control of chemoresistance and minimal residual disease in acute leukemias.
Financial support and sponsorship
The authors are employees of the University of Bradford.
Conflicts of interest
There are no conflicts of interest.
References
| 1 | Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D, et al. The bone marrow niche, stem cells, and leukemia: Impact of drugs, chemicals, and the environment. Ann N Y Acad Sci 2014;1310:7-31. |
| 2 | Jacamo R, Andreeff M. Bone marrow microenvironment-mediated resistance to chemotherapy in leukemia. J Nat Sci 2015;1:145. |
| 3 | Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT, et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 2005;106:1232-9. |
| 4 | Tabe Y, Konopleva M. Advances in understanding the leukaemia microenvironment. Br J Haematol 2014;164:767-78. |
| 5 | Jude CD, Gaudet JJ, Speck NA, Ernst P. Leukemia and hematopoietic stem cells: Balancing proliferation and quiescence. Cell Cycle 2008;7:586-91. |
| 6 | Lane SW. Bad to the bone. Blood 2012;119:323-5. |
| 7 | Fragoso R, Pereira T, Wu Y, Zhu Z, Cabeçadas J, Dias S. VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood 2006;107:1608-16. |
| 8 | Casalou C, Fragoso R, Nunes JF, Dias S. VEGF/PLGF induces leukemia cell migration via P38/ERK1/2 kinase pathway, resulting in rho GTPases activation and caveolae formation. Leukemia 2007;21:1590-4. |
| 9 | Rashidi A, Uy GL. Targeting the microenvironment in acute myeloid leukemia. Curr Hematol Malig Rep 2015;10:126-31. |
| 10 | Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010;464:852-7. |
| 11 | Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-7. |
| 12 | Ayala F, Dewar R, Kieran M, Kalluri R. Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia 2009;23:2233-41. |
| 13 | Bradstock KF, Gottlieb DJ. Interaction of acute leukemia cells with the bone marrow microenvironment: Implications for control of minimal residual disease. Leuk Lymphoma 1995;18:1-6. |
| 14 | Bendall LJ, Daniel A, Kortlepel K, Gottlieb DJ. Bone marrow adherent layers inhibit apoptosis of acute myeloid leukemia cells. Exp Hematol 1994;22:1252-60. |
| 15 | González-Amaro R, Sánchez-Madrid F. Cell adhesion molecules: Selectins and integrins. Crit Rev Immunol 1999;19:389-429. |
| 16 | Hynes RO. Integrins: Bidirectional, allosteric signaling machines. Cell 2002;110:673-87. |
| 17 | Zent R, Pozzi A. Cell-Extracellular Matrix Interactions in Cancer. Vol. 7. New York: Springer; 2010. |
| 18 | Luo BH, Springer TA. Integrin structures and conformational signaling. Curr Opin Cell Biol 2006;18:579-86. |
| 19 | Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem 2000;275:21785-8. |
| 20 | Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 2005;21:381-410. |
| 21 | Sheldrake HM, Patterson LH. Function and antagonism of beta3 integrins in the development of cancer therapy. Curr Cancer Drug Targets 2009;9:519-40. |
| 22 | Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11-25. |
| 23 | Humphries MJ. Integrin structure. Biochem Soc Trans 2000;28:311-39. |
| 24 | Chen J, Alexander JS, Orr AW. Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis. Int J Cell Biol 2012;2012:853703. |
| 25 | Goodman SL, Picard M. Integrins as therapeutic targets. Trends Pharmacol Sci 2012;33:405-12. |
| 26 | Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 2000;156:1345-62. |
| 27 | Liang D, Wang X, Mittal A, Dhiman S, Hou SY, Degenhardt K, et al. Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis. Dev Biol 2014;395:232-44. |
| 28 | Janouskova H, Maglott A, Leger DY, Bossert C, Noulet F, Guerin E, et al. Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma. Cancer Res 2012;72:3463-70. |
| 29 | Müller U, Wang D, Denda S, Meneses JJ, Pedersen RA, Reichardt LF. Integrin alpha8beta1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis. Cell 1997;88:603-13. |
| 30 | Goodman L, Zallocchi M. Integrin α8 and pcdh15 act as a complex to regulate cilia biogenesis in sensory cells. J Cell Sci 2017;130:3698-712. |
| 31 | Ryu J, Koh Y, Park H, Kim DY, Kim DC, Byun JM, et al. Highly expressed integrin-α8 induces epithelial to mesenchymal transition-like features in multiple myeloma with early relapse. Mol Cells 2016;39:898-908. |
| 32 | Khalifeh-Soltani A, Ha A, Podolsky MJ, McCarthy DA, McKleroy W, Azary S, et al. a8β1 integrin regulates nutrient absorption through an mfge8-PTEN dependent mechanism. Elife 2016;5. pii: e13063. |
| 33 | Quinn MJ, Byzova TV, Qin J, Topol EJ, Plow EF. Integrin alphaIIbbeta3 and its antagonism. Arterioscler Thromb Vasc Biol 2003;23:945-52. |
| 34 | Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alphavbeta3 for angiogenesis. Science 1994;264:569-71. |
| 35 | Anderson HC. An antagonist of osteoclast integrins prevents experimental osteoporosis. J Clin Invest 1997;99:2059. |
| 36 | Nisato RE, Tille JC, Jonczyk A, Goodman SL, Pepper MS. Alphavbeta3 and alphavbeta5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 2003;6:105-19. |
| 37 | Koivisto L, Bi J, Häkkinen L, Larjava H. Integrin αvβ6: Structure, function and role in health and disease. Int J Biochem Cell Biol 2018;99:186-96. |
| 38 | Wang J, Dong X, Zhao B, Li J, Lu C, Springer TA. Atypical interactions of integrin αVβ8 with pro-TGF-β1. Proc Natl Acad Sci U S A 2017;114:E4168-74. |
| 39 | Worthington JJ, Kelly A, Smedley C, Bauché D, Campbell S, Marie JC, et al. Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Immunity 2015;42:903-15. |
| 40 | Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. Beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 2002;129:2891-903. |
| 41 | Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, et al. The αvβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med 2015;7:288ra79. |
| 42 | Adorno-Cruz V, Liu H. Regulation and functions of integrin α2 in cell adhesion and disease. Genes Dis 2019;6:16-24. |
| 43 | Mitroulis I, Alexaki VI, Kourtzelis I, Ziogas A, Hajishengallis G, Chavakis T. Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 2015;147:123-35. |
| 44 | Bertoni A, Alabiso O, Galetto AS, Baldanzi G. Integrins in T cell physiology. Int J Mol Sci 2018;19. pii: E485. |
| 45 | Vanderslice P, Woodside DG, Caivano AR, Decker ER, Munsch CL, Sherwood SJ, et al. Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1. Biochem Biophys Res Commun 2010;400:619-24. |
| 46 | Imai Y, Shimaoka M, Kurokawa M. Essential roles of VLA-4 in the hematopoietic system. Int J Hematol 2010;91:569-75. |
| 47 | Yazlovitskaya EM, Viquez OM, Tu T, De Arcangelis A, Georges-Labouesse E, Sonnenberg A, et al. The laminin binding α3 and α6 integrins cooperate to promote epithelial cell adhesion and growth. Matrix Biol 2019;77:101-16. |
| 48 | Krebsbach PH, Villa-Diaz LG. The role of integrin α6 (CD49f) in stem cells: More than a conserved biomarker. Stem Cells Dev 2017;26:1090-9. |
| 49 | Schaff M, Tang C, Maurer E, Bourdon C, Receveur N, Eckly A, et al. Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation 2013;128:541-52. |
| 50 | Walling BL, Kim M. LFA-1 in T cell migration and differentiation. Front Immunol 2018;9:952. |
| 51 | Takada Y, Ye X, Simon S. The integrins. Genome Biol 2007;8:215. |
| 52 | Hamidi H, Ivaska J. Every step of the way: Integrins in cancer progression and metastasis. Nat Rev Cancer 2018;18:533-48. |
| 53 | Hamidi H, Pietilä M, Ivaska J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer 2016;115:1017-23. |
| 54 | Longmate W, DiPersio CM. Beyond adhesion: Emerging roles for integrins in control of the tumor microenvironment. F1000Res 2017;6:1612. |
| 55 | Paolillo M, Schinelli S. Integrins and exosomes, a dangerous liaison in cancer progression. Cancers (Basel) 2017;9. pii: E95. |
| 56 | Wu YJ, Pagel MA, Muldoon LL, Fu R, Neuwelt EA. High αv integrin level of cancer cells is associated with development of brain metastasis in athymic rats. Anticancer Res 2017;37:4029-40. |
| 57 | Johansen S, Brenner AK, Bartaula-Brevik S, Reikvam H, Bruserud Ø. The possible importance of β3 integrins for leukemogenesis and chemoresistance in acute myeloid leukemia. Int J Mol Sci 2018;19. pii: E251. |
| 58 | Röselová P, Obr A, Holoubek A, Grebeňová D, Kuželová K. Adhesion structures in leukemia cells and their regulation by src family kinases. Cell Adh Migr 2018;12:286-98. |
| 59 | Becker PS, Appelbaum FR. VLA-4 function and prognosis in acute myeloid leukemia. In: Andreeff M, editor. Targeted Therapy of Acute Myeloid Leukemia. New York: Springer New York; 2015. p. 627-35. |
| 60 | Yi H, Zeng D, Shen Z, Liao J, Wang X, Liu Y, et al. Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring fms-like tyrosine kinase-3 internal tandem duplication mutations: Implications for microenvironment influence on sorafenib sensitivity. Oncotarget 2016;7:40387-97. |
| 61 | Kong QL, An XZ, Guan XM, Ma YM, Li PF, Liang SY, et al. Expression of β-integrin family members in children with T-cell acute lymphoblastic leukemia. Zhongguo Dang Dai Er Ke Za Zhi 2017;19:620-6. |
| 62 | Vacca A, Ria R, Presta M, Ribatti D, Iurlaro M, Merchionne F, et al. Alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells. Exp Hematol 2001;29:993-1003. |
| 63 | Al-Asadi MG, Brindle G, Castellanos M, May ST, Mills KI, Russell NH, et al. A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells. Oncotarget 2017;8:111405-18. |
| 64 | Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007;25:1315-21. |
| 65 | Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, Wilhelm JS, et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 2008;13:483-95. |
| 66 | Mohr S, Doebele C, Comoglio F, Berg T, Beck J, Bohnenberger H, et al. Hoxa9 and meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia. Cancer Cell 2017;31:549-62. |
| 67 | Miller PG, Al-Shahrour F, Hartwell KA, Chu LP, Järås M, Puram RV, et al. In vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell 2013;24:45-58. |
| 68 | Shah CA, Bei L, Wang H, Altman JK, Platanias LC, Eklund EA. Cooperation between alphavbeta3 integrin and the fibroblast growth factor receptor enhances proliferation of hox-overexpressing acute myeloid leukemia cells. Oncotarget 2016;7:54782-94. |
| 69 | Gruszka AM, Valli D, Restelli C, Alcalay M. Adhesion deregulation in acute myeloid leukaemia. Cells 2019;8. pii: E66. |
| 70 | Shen ZH, Zeng DF, Wang XY, Ma YY, Zhang X, Kong PY. Targeting of the leukemia microenvironment by c(RGDfV) overcomes the resistance to chemotherapy in acute myeloid leukemia in biomimetic polystyrene scaffolds. Oncol Lett 2016;12:3278-84. |
| 71 | Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J 2009;28:1351-61. |
| 72 | Katrancha ED, Gonzalez LS 3rd. Trauma-induced coagulopathy. Crit Care Nurse 2014;34:54-63. |
| 73 | Kononczuk J, Surazynski A, Czyzewska U, Prokop I, Tomczyk M, Palka J, et al. aIIbβ3-integrin ligands: Abciximab and eptifibatide as proapoptotic factors in MCF-7 human breast cancer cells. Curr Drug Targets 2015;16:1429-37. |
| 74 | Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics 2011;1:154-88. |
| 75 | Trikha M, Timar J, Lundy SK, Szekeres K, Tang K, Grignon D, et al. Human prostate carcinoma cells express functional alphaIIb(beta)3 integrin. Cancer Res 1996;56:5071-8. |
| 76 | Zhai J, Wang Y, Xu C, Zheng L, Wang M, Feng W, et al. Facile approach to observe and quantify the α(IIb)β3 integrin on a single-cell. Anal Chem 2015;87:2546-9. |
| 77 | Hirt A, Luethy AR, Mueller B, Gugler E, Wagner HP. Acute megakaryoblastic leukemia in children identified by immunological marker studies. Am J Pediatr Hematol Oncol 1990;12:27-33. |
| 78 | Ylanne J, Cheresh DA, Virtanen I. Localization of β1, β3, α5, αv, and αIIb subunits of the integrin family in spreading human erythroleukemia cells. Blood 1990;76:570-7. |
| 79 | Berger MD, Heini AD, Seipel K, Mueller B, Angelillo-Scherrer A, Pabst T. Increased fibrinogen levels at diagnosis are associated with adverse outcome in patients with acute myeloid leukemia. Hematol Oncol 2017;35:789-96. |
| 80 | Zauli G, Bassini A, Vitale M, Gibellini D, Celeghini C, Caramelli E, et al. Thrombopoietin enhances the alphaIIbbeta3-dependent adhesion of megakaryocytic cells to fibrinogen or fibronectin through PI 3 kinase. Blood 1997;89:883-95. |
| 81 | Shelly C, Petruzzelli L, Herrera R. K562 cells resistant to phorbol 12-myristate 13-acetate-induced growth arrest: Dissociation of mitogen-activated protein kinase activation and egr-1 expression from megakaryocyte differentiation. Cell Growth Differ 2000;11:501-6. |
| 82 | Galletti P, Soldati R, Pori M, Durso M, Tolomelli A, Gentilucci L, et al. Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives. Eur J Med Chem 2014;83:284-93. |
| 83 | Serini G, Valdembri D, Bussolino F. Integrins and angiogenesis: A sticky business. Exp Cell Res 2006;312:651-8. |
| 84 | Li R, Maminishkis A, Zahn G, Vossmeyer D, Miller SS. Integrin alpha5beta1 mediates attachment, migration, and proliferation in human retinal pigment epithelium: Relevance for proliferative retinal disease. Invest Ophthalmol Vis Sci 2009;50:5988-96. |
| 85 | Schaffner F, Ray AM, Dontenwill M. Integrin α5β1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancers (Basel) 2013;5:27-47. |
| 86 | Jin H, Varner J. Integrins: Roles in cancer development and as treatment targets. Br J Cancer 2004;90:561-5. |
| 87 | Yi L, Hu Q, Zhou J, Liu Z, Li H. Alternative splicing of ikaros regulates the FUT4/LeX-α5β1 integrin-FAK axis in acute lymphoblastic leukemia. Biochem Biophys Res Commun 2019;510:128-34. |
| 88 | Dutta A, Sen T, Chatterjee A. Culture of K562 human myeloid leukemia cells in presence of fibronectin expresses and secretes MMP-9 in serum-free culture medium. Int J Clin Exp Pathol 2010;3:288-302. |
| 89 | Bachsais M, Naddaf N, Yacoub D, Salti S, Alaaeddine N, Aoudjit F, et al. The interaction of CD154 with the α5β1 integrin inhibits fas-induced T cell death. PLoS One 2016;11:e0158987. |
| 90 | Hu Z, Slayton WB. Integrin VLA-5 and FAK are good targets to improve treatment response in the Philadelphia chromosome positive acute lymphoblastic leukemia. Front Oncol 2014;4:112. |
| 91 | De Toni-Costes F, Despeaux M, Bertrand J, Bourogaa E, Ysebaert L, Payrastre B, et al. A new alpha5beta1 integrin-dependent survival pathway through GSK3beta activation in leukemic cells. PLoS One 2010;5:e9807. |
| 92 | Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003;9:1158-65. |
| 93 | Madamanchi A, Santoro SA, Zutter MM. a2β1 integrin. Adv Exp Med Biol 2014;819:41-60. |
| 94 | Lian XY, Zhang W, Wu DH, Ma JC, Zhou JD, Zhang ZH, et al. Methylation-independent ITGA2 overexpression is associated with poor prognosis in de novo acute myeloid leukemia. J Cell Physiol 2018;233:9584-93. |
| 95 | Liu X, Liang Z, Gao K, Li H, Zhao G, Wang S, et al. MicroRNA-128 inhibits EMT of human osteosarcoma cells by directly targeting integrin α2. Tumour Biol 2016;37:7951-7. |
| 96 | Hall CL, Keller ET. Analysis of integrin alpha2beta1 (α2β1) expression as a biomarker of skeletal metastasis. In: Patel VB, Preedy VR, editors. Biomarkers in Bone Disease. Dordrecht: Springer Netherlands; 2017. p. 487-506. |
| 97 | Naci D, El Azreq MA, Chetoui N, Lauden L, Sigaux F, Charron D, et al. a2β1 integrin promotes chemoresistance against doxorubicin in cancer cells through extracellular signal-regulated kinase (ERK). J Biol Chem 2012;287:17065-76. |
| 98 | Berrazouane S, Boisvert M, Salti S, Mourad W, Al-Daccak R, Barabé F, et al. Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia. Cell Death Dis 2019;10:357. |
| 99 | Barry ST, Ludbrook SB, Murrison E, Horgan CM. Analysis of the alpha4beta1 integrin-osteopontin interaction. Exp Cell Res 2000;258:342-51. |
| 100 | Clements JM, Newham P, Shepherd M, Gilbert R, Dudgeon TJ, Needham LA, et al. Identification of a key integrin-binding sequence in VCAM-1 homologous to the LDV active site in fibronectin. J Cell Sci 1994;107(Pt 8):2127-35. |
| 101 | Chigaev A, Wu Y, Williams DB, Smagley Y, Sklar LA. Discovery of very late antigen-4 (VLA-4, alpha4beta1 integrin) allosteric antagonists. J Biol Chem 2011;286:5455-63. |
| 102 | Bae MH, Oh SH, Park CJ, Lee BR, Kim YJ, Cho YU, et al. VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia. Ann Hematol 2015;94:1631-8. |
| 103 | Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 2013;121:1814-8. |
| 104 | Hsieh YT, Gang EJ, Shishido SN, Kim HN, Pham J, Khazal S, et al. Effects of the small-molecule inhibitor of integrin α4, TBC3486, on pre-B-ALL cells. Leukemia 2014;28:2101-4. |
| 105 | Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1100-8. |
| 106 | Butzkueven H, Kappos L, Pellegrini F, Trojano M, Wiendl H, Patel RN, et al. Efficacy and safety of natalizumab in multiple sclerosis: Interim observational programme results. J Neurol Neurosurg Psychiatry 2014;85:1190-7. |
| 107 | Duchartre Y, Bachl S, Kim HN, Gang EJ, Lee S, Liu HC, et al. Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies. PLoS One 2017;12:e0187684. |
| 108 | Khalkar P, Ali HA, Codó P, Argelich ND, Martikainen A, Arzenani MK, et al. Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis. Free Radic Biol Med 2018;117:247-57. |
| 109 | Ruan Y, Gang EJ, Kim HN, Parekh C, Abdel-Azim H, Bhojwani D, et al. AVA4746, an orally available, clinical grade antagonist of integrin α4, sensitizes pre-B cell acute lymphoblastic leukemia to chemotherapy. Blood 2016;128:2765. |
| 110 | Reynolds LE, D'Amico G, Lechertier T, Papachristodoulou A, Muñoz-Félix JM, De Arcangelis A, et al. Dual role of pericyte α6β1-integrin in tumour blood vessels. J Cell Sci 2017;130:1583-95. |
| 111 | Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 2018;560:55-60. |
| 112 | Yu X, Zhang H, Yuan M, Zhang P, Wang Y, Zheng M, et al. Identification and characterization of a murine model of BCR-ABL1+acute B-lymphoblastic leukemia with central nervous system metastasis. Oncol Rep 2019;42:521-32. |
| 113 | Yamakawa N, Kaneda K, Saito Y, Ichihara E, Morishita K. The increased expression of integrin α6 (ITGA6) enhances drug resistance in EVI1(high) leukemia. PLoS One 2012;7:e30706. |
| 114 | Reina M, Espel E. Role of LFA-1 and ICAM-1 in cancer. Cancers (Basel) 2017;9. pii: E153. |
| 115 | Phongpradist R, Chittasupho C, Okonogi S, Siahaan T, Anuchapreeda S, Ampasavate C, et al. LFA-1 on leukemic cells as a target for therapy or drug delivery. Curr Pharm Des 2010;16:2321-30. |
| 116 | Tanaka Y, Mine S, Figdor CG, Wake A, Hirano H, Tsukada J, et al. Constitutive chemokine production results in activation of leukocyte function-associated antigen-1 on adult T-cell leukemia cells. Blood 1998;91:3909-19. |
| 117 | Holland M, Castro FV, Alexander S, Smith D, Liu J, Walker M, et al. RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia. Blood 2011;118:638-49. |
| 118 | Zeng DF, Zhang J, Zhu LD, Kong PY, Li JP, Zhang X, et al. Analysis of drug resistance-associated proteins expressions of patients with the recurrent of acute leukemia via protein microarray technology. Eur Rev Med Pharmacol Sci 2014;18:537-43. |
| 119 | Boztug H, Schumich A, Pötschger U, Mühlegger N, Kolenova A, Reinhardt K, et al. Blast cell deficiency of CD11a as a marker of acute megakaryoblastic leukemia and transient myeloproliferative disease in children with and without Down syndrome. Cytometry B Clin Cytom 2013;84:370-8. |
| 120 | DiFranco KM, Gupta A, Galusha LE, Perez J, Nguyen TV, Fineza CD, et al. Leukotoxin (Leukothera®) targets active leukocyte function antigen-1 (LFA-1) protein and triggers a lysosomal mediated cell death pathway. J Biol Chem 2012;287:17618-27. |
| 121 | Gupta A, Le A, Belinka BA, Kachlany SC.In vitro synergism between LFA-1 targeting leukotoxin (Leukothera™) and standard chemotherapeutic agents in leukemia cells. Leuk Res 2011;35:1498-505. |
| 122 | Engl T, Relja B, Marian D, Blumenberg C, Müller I, Beecken WD, et al. CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 2006;8:290-301. |
| 123 | Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: Role of the CXCL12/CXCR4 axis. Onco Targets Ther 2013;6:1347-61. |
| 124 | Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 2001;19:453-66. |
| 125 | Sun YX, Fang M, Wang J, Cooper CR, Pienta KJ, Taichman RS. Expression and activation of alphavbeta3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate 2007;67:61-73. |
| 126 | Yu Y, Shi X, Shu Z, Xie T, Huang K, Wei L, et al. Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin β1 and β3 expressions. Oncol Res 2013;21:217-25. |
| 127 | Pillozzi S, Bernini A, Spiga O, Lelli B, Petroni G, Bracci L, et al. Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow-induced chemoresistance in acute leukemias. Oncol Rep 2019;41:312-24. |
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