Abstract 3851: NUP98-PHF23 (NP23) binds H3K4me3 and causes a wide spectrum of leukemias, including AML, T-ALL, and pre-B1 ALL.

Abstract

Abstract Nucleoporin 98 (NUP98) fusions have been associated with acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, and T-cell acute lymphoblastic leukemia (T-ALL). An AML patient with a t(11;17)(p15;p13) chromosome translocation was found to have a novel gene fusion between NUP98 and plant homeodomain (PHD) finger 23 (PHF23). PHF23 has been reported to act as a reader of tri-methylated histone 3 lysine 4 (H3K4me3) marks, suggesting that PHF23 may function in chromatin regulation and that the NP23 fusion protein may play a role in aberrant chromatin modification. To determine the oncogenic potential of NP23, we generated mice that expressed the NP23 fusion in hematopoietic tissues. We characterized two founder lines (C10 and B10) that expressed the NP23 fusion. The C10 line principally developed AML that closely resembled the human disease, with increased blasts in the blood and bone marrow, widespread organ infiltration, and myeloid immunophenotype. Onset of disease was as early as 4.5 months, and 70 percent of the NP23 mice succumbed to leukemia by 12 months of age. The B10 line developed a wider spectrum of leukemias with similar age of onset and penetrance. The B10 mice predominantly developed T-ALL and AML. Interestingly, four B10 mice developed a previously unreported form of ALL that was of pre-B1 (B220−/CD19+/AA4.1+) origin, indicating that the NP23 protein is oncogenic in multiple hematopoietic lineages. Gene expression arrays and RQ-PCR revealed Hoxa5, a7, a9 and a10 to be overexpressed from 10-1000 fold in both AML and T-ALL, as well as in hematopoietic tissues from clinically healthy NP23 transgenic mice. Premalignant, clinically healthy mice showed aberrant hematopoietic stem and progenitor cell (HSPC) populations. Bone marrow lineage negative (Linneg) cells were decreased by half that of WT littermates, and LSK (Linneg/Sca1+/cKit+) cells were further reduced by 3-fold. NP23 thymi were dramatically smaller in size with an average 5-fold reduction in thymocytes, which was associated with a partial differentiation block of thymocytes at the DN2 stage. B2 pre-B-cells were significantly reduced, by 50%, compared to WT controls. B1-progenitor B-cells (Linneg/CD19+/AA4.1+) in the bone marrow were reduced by 30% in the bone marrow and mature B1 B-cells (B220−/CD19+/IgM+) of the peritoneal cavity were further decreased to half that of WT. We also performed genome wide NP23 and H3K4me3 ChIP-seq which identified a core set of H3K4me3 marked genes bound by the NP23 fusion protein that were overexpressed in both myeloid and T-cell lineages. The NP23 oncogene is capable of promoting cell lineage-independent leukemic transformation, and will be useful in identifying oncoproteins and transformation pathways that involve chromatin deregulation and HSPC gene signatures such as those of the HOXA cluster. Citation Format: Sheryl M. Gough, Fan Lee, Yang Jo Chung, Robert L. Walker, Fan Yang, Jack Zhu, Yi Ning, Paul S. Meltzer, Peter D. Aplan. NUP98-PHF23 (NP23) binds H3K4me3 and causes a wide spectrum of leukemias, including AML, T-ALL, and pre-B1 ALL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3851. doi:10.1158/1538-7445.AM2013-3851