CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells

By R. Majeti, M. Chao, Ash A. Alizadeh, W. Pang, Siddhartha Jaiswal, Kenneth D. Gibbs, N. Rooijen, Irving L. Weissman. Cell, 2009

1,689 citations recorded by the source corpus.

SUMMARY Acute myelogenous leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells (LSC). We hypothesized that increased CD47 expression on human AML LSC contributes to pathogenesis by inhibiting their phagocytosis through the interaction of CD47 with an inhibitory receptor on phagocytes. We found that CD47 was more highly expressed on AML LSC than their normal counterparts, and that increased CD47 expression predicted worse overall survival in 3 independent cohorts of adult AML patients. Furthermore, blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Finally, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted AML LSC. In summary, increased CD47 expression is an independent poor prognostic factor that can be targeted on human AML stem cells with blocking monoclonal antibodies capable of enabling phagocytosis of LSC.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/9dcee66645ee367724ae761eebae78a410e82044

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Citations in the corpus

The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors (2012, background): “We previously demonstrated that blockade of CD47-mediated SIRPα signaling using targeted monoclonal antibodies (mAbs) induced the phagocytosis of leukemia, lymphoma, and bladder cancer cells by human and mouse macrophages (5, 16, 17, 26).”
MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. (2009, background): “Surprisingly, despite the enormous biological importance of CD47 (Jaiswal et al., 2009; Majeti et al., 2009), details of its regulation are largely unknown.”
Immune parameters affecting the efficacy of chemotherapeutic regimens (2011, background): “correlated with high expression of CD47, a 'don't eat me' self protection signal that negatively affects the prognosis of AML patients”
CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. (2009, positive): “In fact, we show in a companion paper (Majeti et al., 2009 [this issue of Cell]), that anti-CD47 blocked CD47hi human AML cells are phagocytosed by macrophages, without first becoming apoptotic.”
An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure. (2015, background): “Since human tumor cells treated with anti-CD47 mAb are killed through engulfment by macrophages [88], its clinical application for cancer patients is considered.”
Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia (2012, methodology): “Rare residual HSCs in the eTranslationalMedicine.org 29 August 2012 Vol 4 Issue 149 149ra118 1 Lin−CD34+CD38− fraction were isolated from these samples by fluorescenceactivated cell sorting (FACS) on the basis of their lack of expression of the AML marker TIM3 and/or a new marker CD99 (Fig.”
Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47 (2010, methodology): “The CD47-SIRPa interaction can be therapeutically targetedwith amonoclonal blocking antibody against CD47, which enables phagocytosis of acute myeloid leukemia (AML), bladder cancer, andnon-Hodgkin’s lymphoma (NHL) cells in vitro and in vivo (6, 8, 9).”
Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response (2013, background): “We have demonstrated the therapeutic efficacy of anti-CD47 blocking mAbs against xenograft human cancers growing in immunodeficient mice, including cancers such as leukemia (5, 13), lymphoma (14), and multiple myeloma (15), solid tumors, including breast, colon, prostate, and bladder cancers, and sa”