Abstract IA04: Using genome editing to model MLL rearranged leukemias

Abstract

Abstract MLL rearranged leukemias, particularly those associated with infant acute lymphoblastic leukemias, continue to have a generally poorer prognosis than other childhood leukemias. Improved understanding of these leukemias has been gained by using transgenic mouse models and retroviral transduction of human cells but each of these approaches has well recognized limitations. With the recent development of an expanded genome editing toolbox, it is now possible to use genome editing in primary human hematopoietic stem and progenitor cells (HSPCs) to directly re-create genomic rearrangements, including those involving the MLL gene. Using these tools we have generated MLL-AF4 and MLL-AF9 translocations in HSPCs and studied the biologic properties of these cells. Moreover, we have further used genome editing of HSPCs to knock-in the AF9 fusion partner into the MLL locus to create the MLL-AF9 fusion. When the modified HSPCs were transplanted into immunodeficient mice (NSG), these modified cells gave rise to ALL, mixed phenotype leukemias, and AML. These results now give a powerful new way to study the developmental biology and pathogenesis of MLL rearranged leukemias and provide a proof-of-concept of how genome editing of human HSPCs can be used to study a wide variety of hematologic disorders. Citation Format: Erin Breese, Corina Buechele, Michael Cleary, Matthew Porteus. Using genome editing to model MLL rearranged leukemias. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA04.