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

Duchartre, Yann; Bachl, Stefanie; Kim, Hye Na; Gang, Eun Ji; Lee, Solah; Liu, Hsiao‐Chuan; Shung, K. Kirk; Xu, Ruth; Kruse, Aaron; Tachas, George; Bönig, Halvard-Björn; Kim, Yong-Mi

doi:10.1371/journal.pone.0187684

Cited by 9 publications

(7 citation statements)

References 24 publications

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“…Our studies also showed that both deletion and inhibition with natalizumab of integrin a4 sensitize primary B-ALL cells to chemotherapy (175). Furthermore, the CD49d antisense drug ATL1102 efficiently downregulated the CD49d mRNA level of B-ALL in vitro (176). Anti-VLA-4 antibodies (SG/73, SG/17) were shown to increase chemosensitivity in human AML cells and eradicate minimal residual disease (MRD) in experimental mice when combined with chemotherapy (6).…”

Section: Integrin a 4 (Cd49d)mentioning

confidence: 59%

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

et al. 2020

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The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell–cell or cell–extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.

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Section: Integrin a 4 (Cd49d)mentioning

confidence: 59%

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

et al. 2020

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“…The functions of VLA-4 are central for the dissemination and drug resistance in ALL cells, and VLA-4 inhibition with blocking antibodies (Natalizumab) or small molecules (TBC3486) sensitizes leukemic cells to conventional therapies and improves survival in vivo models [ 34 , 35 ]. Recently, it has been shown that targeting VLA-4 with antisense drugs fails to improve survival in mouse model of ALL [ 36 ], supporting the idea that blocking the integrin and its molecular pathways has to continue being improved. Several molecules, such as myosin IIA, RhoA and Rap1b, translate integrins signals into cytoskeletal changes affecting the cell capacity to squeeze through HUVEC cells [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells

Madrazo

Ruano

Abad

et al. 2018

Cancers

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. As ALL progresses, leukemic cells cross the endothelial barrier and infiltrate other tissues. Epigenetic enzymes represent novel therapeutic targets in hematological malignancies, and might contribute to cells’ capacity to migrate across physical barriers. Although many molecules drive this process, the role of the nucleus and its components remain unclear. We report here, for the first time, that the expression of G9a (a histone methyltransferase related with gene silencing) correlates with the expression of the integrin subunit α4 in children with ALL. We have demonstrated that G9a depletion or its inhibition with BIX01294 abrogated the ability of ALL cells to migrate through an endothelial monolayer. Moreover, G9a-depleted and BIX01294-treated cells presented bigger nuclei and more adherent phenotype than control cells on endothelial monolayers. Blocking G9a did not affect the cell cytoskeleton or integrin expression of ALL cell lines, and only its depletion reduced slightly F-actin polymerization. Similarly to the transendothelial migration, G9a inhibition impaired the cell migration induced by the integrin VLA-4 (α4β1) of primary cells and ALL cell lines through narrow spaces in vitro. Our results suggest a cellular connection between G9a and VLA-4, which underlies novel functions of G9a during ALL cell migration.

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“…In ALL, the small molecule inhibitor of the α4 subunit TBC3486 blocks ALL cell adhesion, reduces α4 expression, sensitizes B-ALL cells for death in vitro and extends survival time in a B-ALL xenograft model (212). In addition, ATL1102, an α4 antisense oligonucleotide developed to treat multiple sclerosis, downregulates the expression of α4 and β1 subunits in the B-ALL Kasumi-2 cell line in vitro (213). Unfortunately, this antisense oligonucleotide fails to downregulate α4 expression and to improve survival in a mouse model of B-ALL (213), indicating that antisense drugs must be improved for clinical application in this malignancy.…”

Section: Trafficking Molecules As Therapeutic Targets In Hematologic mentioning

confidence: 99%

“…In addition, ATL1102, an α4 antisense oligonucleotide developed to treat multiple sclerosis, downregulates the expression of α4 and β1 subunits in the B-ALL Kasumi-2 cell line in vitro (213). Unfortunately, this antisense oligonucleotide fails to downregulate α4 expression and to improve survival in a mouse model of B-ALL (213), indicating that antisense drugs must be improved for clinical application in this malignancy. Interestingly, as there is a functional link between α4β1 and the histone methyltransferase G9a, which regulates migration of Jurkat (T-ALL) cells (214), the G9a inhibitor CM-272 has been reported to block cell proliferation and infiltration in an in vivo xenograft model (215).…”

Section: Trafficking Molecules As Therapeutic Targets In Hematologic mentioning

confidence: 99%

Molecular Players in Hematologic Tumor Cell Trafficking

2019

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The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression. A common feature of these neoplasias is the homing and infiltration of blood cancer cells into the bone marrow (BM), which favors growth and survival of the malignant cells. MM cells traffic between different BM niches and egress from BM at late disease stages. Besides the BM, CLL cells commonly home to lymph nodes (LNs) and spleen. Likewise, ALL cells also infiltrate extramedullary organs, such as the central nervous system, spleen, liver, and testicles. The α4β1 integrin and the chemokine receptor CXCR4 are key molecules for MM, ALL, and CLL cell trafficking into and out of the BM. In addition, the chemokine receptor CCR7 controls CLL cell homing to LNs, and CXCR4, CCR7, and CXCR3 contribute to ALL cell migration across endothelia and the blood brain barrier. Some of these receptors are used as diagnostic markers for relapse and survival in ALL patients, and their level of expression allows clinicians to choose the appropriate treatments. In CLL, elevated α4β1 expression is an established adverse prognostic marker, reinforcing its role in the disease expansion. Combining current chemotherapies with inhibitors of malignant cell trafficking could represent a useful therapy against these neoplasias. Moreover, immunotherapy using humanized antibodies, CAR-T cells, or immune check-point inhibitors together with agents targeting the migration of tumor cells could also restrict their survival. In this review, we provide a view of the molecular players that regulate the trafficking of neoplastic cells during development and progression of MM, CLL, and ALL, together with current therapies that target the malignant cells.

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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

Cited by 9 publications

References 24 publications

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells

Molecular Players in Hematologic Tumor Cell Trafficking

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