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Understanding and Targeting Epigenetic Alterations in Acquired Bone Marrow Failure

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Technical Report,01 May 2012,30 Apr 2016

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Sloan Kettering Institute for Cancer Research New York United States

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Systematic genomic discovery efforts in patients with bone marrow failure due to myelodysplastic syndrome MDS has led to the rapid discovery of recurrent somatic genetic alterations underlying these disorders. Remarkably, a large number of these mutations occur in genes whose function is known, or suspected, to be involved in epigenetic regulation of gene transcription or in RNA splicing. This includes mutations in ASXL1, TET2, and EZH2 as well as mutations in the RNA splicing factors SF3B1, SRSF2, and U2AF1. Over the course of funding of this award we have made major progress in 1 understanding the impact of ASXL1 mutations and loss on chromatin Abdel-Wahab, et al. Cancer Cell 2012, 2 identifying the in vivo biological effects of deletion of Asxl1 and Tet2 alone and in combination with one another Abdel-Wahab, et al. J Exp Med 2013, 3 identified the genome-wide effects of Asxl1 on transcription Abdel-Wahab, et al. J Exp Med 2013 and Abdel-Wahab, O, et al. Leukemia 2013, 4 identified that mutations in the splicing machinery in MDS also may impact the function of epigenetic modifiers Kim, E, et al. Cancer Cell 2015, 5 developed therapeutic approach to target spliceosomal mutant MDS Lee, SCW, et al. Nat Med 2016, and 6 identified a function of ASXL2, a paralog of ASXL1, in normal and malignant hematopoiesis Micol, J-B, et al. Nat Comm 2017.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology

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