Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Hsieh, Yao Te; Gang, Eun Ji; Geng, Huimin; Park, Eugene; Huantes, Sandra; Chudziak, Doreen; Dauber, Katrin; Schaefer, Paul; Scharman, Carlton; Shimada, Hiroyuki; Shojaee, Seyedmehdi; Klemm, Lars; Parameswaran, Reshmi; Loh, Mignon L.; Kang, Eun Suk; Koo, Hong Hoe; Hofmann, Wolf Karsten; Andrade, Jacob; Willman, Cheryl L.; Müschen, Markus; Papayannopoulou, Thalia; Heisterkamp, Nora; Bönig, Halvard; Kim, Yong-Mi

doi:10.1182/blood-2012-01-406272

Cited by 110 publications

(147 citation statements)

References 24 publications

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“…Notably, a recent report showed dramatic improvement of survival of mice transplanted with primary human ALL cells, on combination of Natalizumab, an antifunctional VLA-4 antibody, with chemotherapy. 45 Our data further indicated that coculture with BM-MSCs can also induce NF-kB activation in leukemia cells ( Figure 5E) and that blockade of the VLA-4-VCAM-1 interaction during coculture can impair levels of IL-1a, and to a less extent IL-1b, mRNA expression in REH and OCI-AML3 leukemia cells ( Figure 5C-D). In addition, disruption of the VLA-4-VCAM-1 interaction during coculture impaired the nuclear translocation of NF-kB in BM-MSC ( Figure 5F).…”

Section: Discussionsupporting

confidence: 68%

Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance

Jácamo

Chen

Wang³

et al. 2014

Blood

239

218

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Section: Discussionsupporting

confidence: 68%

Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance

Jácamo

Chen

Wang³

et al. 2014

Blood

239

218

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“…Increased expression of THY1 (Yamazaki et al, 2009) and integrins (Hsieh et al, 2013; Miller et al, 2013) have been noted previously in ALL and Ikzf1 -mutant mouse B-cells (Joshi et al, 2014) but not in Ph + ALL. In gain- and loss-of-function studies, we have shown that upregulation of these genes is a consequence of IKZF1 alterations and directly contributes to enhanced adhesion and self-renewal properties in Ikzf1- altered BCR-ABL1 cells.…”

Section: Discussionsupporting

confidence: 63%

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Churchman¹,

Low²,

Qu³

et al. 2015

Cancer Cell

162

178

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SUMMARY Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

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“…The combination of carboplatin and anti-α4β1 integrin antibodies results in increased ovarian cancer cell death and doubling time in vitro and significantly reduces tumor burden in murine models of platinum-resistant peritoneal disease [155]. Integrin α4 blockade sensitizes resistant human leukemia blasts to acute lymphoblastic leukemia (ALL) chemotherapy (vincristine, dexamethasone, and L-asparaginase) in vitro and its addition to standard ALL chemotherapy prolongs the survival of NOD/SCID recipients of human pre-B ALL cells in vivo [156].…”

Section: Integrins and Cell Adhesion-mediated Drug Resistancementioning

confidence: 99%

Integrins

Sun

Gao

2014

Anti-Cancer Drugs

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Integrins are a large family of cell surface receptors that bind extracellular matrix proteins. The interaction of integrins with extracellular matrix activates a number of intracellular signaling pathways involved in cell proliferation, differentiation, motility, and other essential cell functions. Integrins are critically important to both health and disease. In this review, we first describe the structure, functions, and signaling characteristics of integrins. We then discuss the roles of integrins in cancer progression. Finally, we recapitulate the laboratory and clinical efforts of targeting integrins as effective means of cancer therapy and diagnosis. This comprehensive review could help scientists and clinicians gain a complete understanding of integrins. It could also contribute toward the development of new drugs, new methods of diagnostics, and new treatment of cancers to benefit the patients in clinical practice.

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Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Abstract: Key Points We evaluated interference with integrin alpha4–mediated stromal adhesion as a new acute lymphoblastic leukemia treatment. Integrin alpha4 blockade using natalizumab in combination with chemotherapy sensitizes pre-B acute lymphoblastic leukemia to chemotherapy.

Cited by 110 publications

References 24 publications

Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance

Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

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