Integrin β3 Is a Potential Therapeutic Target in AML

The microenvironmental niche of the bone marrow regulates the survival, differentiation, and function of both normal hematopoietic stem and progenitor cells (HSPC) and leukemia stem cells (LSC). To characterize genes that are specifically essential for acute myeloid leukemia (AML) cells but not normal HSPCs within the context of this microenvironment, Miller and colleagues performed a series of in vivo RNA interference screens. In addition to genes known to be required for LSC survival, the authors identified integrin β3 (Itgb3) as a gene necessary for leukemia growth in a mouse model of AML driven by the mixed-lineage leukemia (MLL)–AF9 oncogenic fusion. Knockdown or genetic deletion of Itgb3 decreased primary leukemia cell growth in vivo and prolonged survival in tumor-bearing mice, suggesting that ITGB3-mediated interaction of LSCs with the bone marrow microenvironment is critical for tumorigenesis. Consistent with this idea, human leukemia cells and primary AML samples were similarly dependent on ITGB3 expression for tumor growth in xenotransplantation assays. Itgb3 downregulation impaired homing of primary leukemia cells to the bone marrow and resulted in enhanced expression of myeloid differentiation markers and reduced expression of LSC gene signatures. In contrast, knockdown or germline deletion of Itgb3 did not affect the growth, differentiation, or engraftment of HSPCs following transplantation, indicating that it is dispensable for normal hematopoiesis. The selective requirement for ITGB3 in leukemia cells was mediated in part through heterodimerization with integrin alpha V (ITGAV) and activation of spleen tyrosine kinase (SYK); expression of constitutively active SYK rescued leukemia growth in the absence of Itgb3, whereas depletion or pharmacologic inhibition of SYK suppressed leukemia cell growth. These results demonstrate the utility of this type of genetic screening approach and suggest the ITGB3 signaling pathway as a potential therapeutic target in AML.

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.

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