Abstract 5108: The role of H2afy in normal and malignant hematopoiesis

Mutations in the spliceosome gene U2AF1 are found in 11% of patients with myelodysplastic syndrome (MDS), a common hematologic malignancy, and at lower frequencies in some solid cancers. We have shown that expression of a common U2AF1 mutant, U2AF1(S34F), causes altered pre-mRNA splicing and abnormal hematopoiesis in mice, including reduced white blood cell counts (WBC) and B-cells, which are phenotypes similar to patients with MDS. We consistently find that expression of mutant U2AF1 results in reduced RNA expression of H2AFY1.1, a splice isoform of H2AFY, in patient samples and mouse hematopoietic cells. H2AFY (also known as macroH2A1) is a histone H2A variant implicated in transcriptional gene regulation, development, and tumorigenesis. This gene encodes two splice isoforms, H2AFY1.1 and H2AFY1.2. Expression of the H2AFY1.1 isoform is also reduced in several solid cancers. We hypothesize that reduced H2AFY1.1 expression contributes to abnormal hematopoiesis induced by mutant U2AF1(S34F). We first characterized hematopoiesis in adult constitutive H2afy knock-out mice (lacking both H2afy1.1 and H2afy1.2 isoforms). We transplanted bone marrow cells from H2afy+/+ or H2afy-/- mice into lethally irradiated congenic recipients to study the hematopoietic cell-intrinsic effects of H2afy loss. At 6 weeks post-transplant, recipients of H2afy-/- bone marrow cells compared to recipients of H2afy+/+ cells exhibited a marked reduction in WBC (5.0 vs. 9.1 K cells/µL, respectively, p Citation Format: Sanghyun Kim, Monique Chavez, Cara Shirai, Matt Walter. The role of H2afy in normal and malignant hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5108.