|Ahead of print publication
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
Helen M Sheldrake,
Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP
Source of Support: None, Conflict of Interest: None
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.
Keywords: Integrin αvβ3, leukemia, microenvironment, α2β1, α4β1, α5β1, α6β1, αIIbβ3
|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 [Epub ahead of print] [cited 2020 May 26]. Available from: http://www.TMEResearch.org/preprintarticle.asp?id=266936
| Introduction|| |
The bone marrow microenvironment controls function, differentiation, and survival of both normal hematopoietic and leukemia cells., Both the vascular and osteoblastic niches are crucial for leukemia cell proliferation, differentiation, and survival.,
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  and CXCR4/CXCL12 signaling, which participates in homing of hematopoietic stem cells and leukemia cells into bone marrow and activates β1 and β3 integrins. However, leukemia cells differ from hematopoietic cells by impairment of regulatory signaling mechanisms governing survival, proliferation, and invasive and dissemination capabilities.,,
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.,,
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. Stromal ligands such as fibronectin (Fn) interact with leukemia blast integrins,, 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. The integrins are, thus, significant cell adhesion molecules,, 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.,
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.
Structurally, integrins are noncovalent heterodimers containing an α and a β glycoprotein subunit.,, Eight β and 18 α subunits combine to form 24 human αβ integrin dimers.,,, These 24 recognized integrin heterodimers are subdivided into arginine–glycine–aspartate acid (RGD)-binding, leukocyte adhesion integrins, collagen-binding, and laminin-binding integrins.
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. 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. Leukocyte adhesion integrins are non-RGD-binding integrins and contain the β2 or α4 subunits.
|Table 1: Ligands and functions of the arginine-glycineaspartic acid-recognizing integrin subfamily|
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|Table 2: Ligands and functions of non-arginine-glycineaspartic acid-binding integrins relevant to acute leukemias|
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Integrins have proved popular targets for disease-modifying therapies, and many analyses have demonstrated their roles in cancer progression,,,,, including leukemia. Here, we review the most significant integrins involved in microenvironment interactions in acute leukemia.
| Integrins in Acute Leukemia|| |
Arginine–glycine–aspartate acid-binding integrins
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.
Adhesion within the marrow microenvironment leads to chemotherapy resistance in AML and other hematologic malignancies by interfering with apoptosis or activating survival pathways. Expression of β3 is crucial for Opn-enhanced chemotherapy insensitivity in AML cells. 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.
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. In AML, αvβ3 is upregulated in dormant cells and increases their adhesion to Vn; 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. MLL-AF9 cells interact with the bone marrow microenvironment, most probably in the endosteal region. This interaction is important for cell survival and affects lineage fate. Expression of β3 and αv has also been confirmed on primary human AML cells with and without MLL rearrangement.
The ITGB3 gene has been identified as essential in human and murine leukemia cells in vivo., 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.
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., 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. 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. 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.,
Targeting the αvβ3/Opn interaction in leukemia cells leads to enhanced chemosensitivity in AML. 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.,
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.
αIIbβ3 is the main membrane protein  and primary adhesion receptor of blood platelets. 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.
αIIbβ3 has also been detected on solid and hematologic tumor cells.,, The β3 integrin expression level on AML cells is comparable with that on endothelial cells associated with solid tumors., αIIbβ3 has high expression in acute megakaryoblastic AML, providing a diagnostic characteristic. αIIb, β1, β3, and α5 are all critical for attaching erythroleukemia cells to Fn.
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. 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. 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. 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. Therefore, combining αllbβ3 and α5β1 inhibition may provide a potential clinical strategy in antileukemia drug development.
α5β1 is a specific receptor for Fn. Both α5β1 and Fn play a significant role in the development of the vascular system during embryogenesis., α5β1 integrin ligation stimulates cell growth and migration during Akt and MAPK activation-mediated signaling pathways. 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.
α5β1 is expressed in T-ALL, where it can mediate interactions with ECM proteins during the transmigration process. Aberrant glycosylation of α5β1 promotes adhesion, downstream signaling, and invasion of ALL cells. 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. 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.
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.
Interactions with Fn controlling chemosensitivity may be mediated by both α5β1 and α4β1., α5β1 can specifically trigger activation of GSK3β via PP2A, thus promoting cell survival under adverse conditions. α4β1 prosurvival signaling involves PI-3K/AKT/Bcl-2., 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 (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  and is also involved in cell survival, migration, invasion, and angiogenesis. Aberrations in α2β1 expression have been shown in a range of different cancers , and in skeletal metastases leading to α2β1's identification as a possible cancer biomarker. 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.
Binding of α2β1 to collagen blocked doxorubicin-induced programmed cell death of T-ALL by inactivating c-Jun N-terminal kinase (JNK). 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. 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. 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 (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., 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.
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. However, adhesion within the bone marrow microenvironment leads to chemotherapy resistance in AML by interfering with apoptosis or activating cell survival pathways., 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. A small-molecule α4β1 inhibitor (TBC3486) was able to prolong survival although it did not fully eradicate leukemia cells, 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. 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.,
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. 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.
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. 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 is a major laminin receptor and a significant mediator in the growth of tumor blood vessels, as well as platelet adhesion and activation in response to laminins. Expression of α6β1 is common in ALL which permits cells to utilize migratory neural pathways from bone marrow to invade the central nervous system.,
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. 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 (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., In T-ALL, αLβ2 is constitutively activated, promoting extravasation.
High αLβ2 expression is associated with brain infiltration  and relapse in both ALL , and AML. However, loss of αL is a specific marker of acute megakaryoblastic leukemia in pediatric patients. Targeting αLβ2 has been proposed as a method of targeting drugs to leukocytes. 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., 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., 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., Both the β3 and β1 integrin subunits in leukemia are involved in homing and attachment of acute leukemia cells to the bone,, and both participate in the common CXCR4/CXCL12 axis.,
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. In acute pediatric leukemias, CXCR4/CXCL12 and β1 are involved in a multiprotein complex mediating chemoresistance. A combination of α4β1 and CXCR4 expression has been proposed as a prognostic biomarker in adult AML. 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. 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.
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.
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[Table 1], [Table 2], [Table 3]