Using retroviral transduced bone marrow, several labs have shown that NUP98-HOXA9, NUP98-HHEX, NUP98-NSD1, and NUP98-TOP1 fusions are leukemogenic, and NUP98-HOXA9 and NHD13 fusions have been shown to be been shown to be leukemogenic in genetically engineered mice. However, a NUP98-TOP1 fusion was at best weakly oncogenic when expressed from a Vav promoter in transgenic mice. In order to better understand the leukemogenicity of NUP98 fused to non-HOX genes, we generated mice that express either a NUP98-RAP1GDS (NRG) or NUP98-PHF23 (NP23) fusion in hematopoietic cells using Vav regulatory elements to direct expression in the hematopoietic compartment. NRG mice were generated and transmitted the transgene in expected Mendellian ratio, and were documented to express the transgene. However, we could discern no hematopoietic abnormalities in these mice. NP23 mice have been generated, and we have followed a large cohort of offspring from two founders. Almost 100% of these mice develop leukemia within 1 year of life. Interestingly, the leukemic phenotype is very broad, including T and B cell leukemias, myeloid leukemias, and erythroid leukemias. We have begun a series of studies, including chromatin immunoprecipitation and gene expression profiling to identify targets of the NP23 fusion. These experiments show that the leukemias are clonal, and frequently activate a cluser of genes within the Hoxa locus, including Hoxa7,9,10,11, and Meis1. In addition, we have identified novel genes, including Gm525, that are overexpressed in the NP23 leukemias. Overexpression of the Hoxa cluster genes was associated with the prsence of active histone marks (H3K4Me3), and the absence of inactive histone marks (H3K27Me2). An abstract describing these findings has been presented, and a manuscript is in preparation. Recent studies have demonstrated that HOXA9 is important for hematopoietic stem cell self-renewal and is one of the most differentially expressed genes in patients with AML and MDS. Indeed, Hoxa cluster genes, especially Hoxa7/9/10, were among the most differentially expressed genes in the NHD13 and CALM-AF10 mice described in previous projects, suggesting that Hoxa9 is an important target for leukemic transformation. Therefore, we have generated mice that express Hoxa9 in hematopoietic cells, using Vav regulatory elements to enable us to compare these mice to the NHD13 mice. Some of the potential founders did not transmit the transgene, despite having >30 pups genotyped, suggesting that the transgene may have been embryonic lethal in these mice. We have euthanized mice with timed pregnancies, and were able to document embryos that were transgenic, further supporting the possibility that the transgene was embryonic lethal in some founders. Two founders were able to transmit the transgene;however, they only expressed levels of the Hoxa9 transgene that were only slightly higher than wild-type controls. Despite this low level of expression, the Hoxa9 mice have developed a leukemic phenotype. At approximately 12 months of age, some of the Hoxa9 mice have developed a precursor T cell lymphoblastic leukemia/lymphoma (pre-T LBL). These pre-T LBLs are clonal and are typically accompanied by spontaneous Notch1 mutations. We are currently characterizing additional tumors, and assaying the Hoxa9 mice for evidence of disordered T cell differentiation prior to the onset of the pre-T LBL. We noted that Lin28b, a gene involved in microRNA metabolism and the stem cell pluripotency, was overexpressed in the NHD13 mice. To determine if this overexpression was related to malignant transformation, we used Vav regulatory elements to express Lin28b in hematopoietic cells. Lin28b transgenic mice develop an aggressive, clonal, lethal peripheral T cell lymphoma, which is associated with release of inflammatory cytokines. The cell of origin shows immunophenotypic and gene expression features consistent with those of T follicular helper (TFH) cells. A manuscript describing these features is currently under review. We tested the ability of SCL, LMO1, and/or SV40 Large T antigen (TAg) to cause leukemia in zebrafish. The rationale for studying zebrafish is that they have a short generation time, high fecundity, small size, large, visible eggs, and visible, ex vivo development;development of T-lymphoid leukemia in fish would also allow comparative genomic approaches to determine common abnormalities and pathways among humans, mice, and fish. We used an Lck promoter from a related teleost fish (Fugu rubripes) to drive expression of genes in the developing fish thymus, and established transgenic lines for SCL, LMO1, and TAg. After 3 years of study, there was no evidence that any of these lines developed lymphoid malignancies. However, the SCL, LMO1, and TAg lines have decreased survival and a markedly increased incidence of seminoma (testicular germ cell tumor). Two different Lck-TAg lines were followed, and showed a cumulative incidence of seminoma of 12 or 16% by 36 months of life. Transgenic SCL and LMO1 fish are also predisposed to seminoma, with a cumulative incidence of 25 and 14 % by 36 months of life. The seminomas showed variable contribution of spermatocyte, spermatid, and spermatogonial components, and expression of genes that have been used as markers for human (AP2a, OCT4) or fish (Sox9a, Vas, Wt1) testicular tumors. We were puzzled by these findings, as we anticipated that the Lck promoter would direct expression exclusively in the thymus. However, the Fugu Lck promoter was promiscuous, and we detected TAg expression in seminomas and testes. A manuscript describing these findings was recently published.

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Chung, Yang Jo; Fry, Terry J; Aplan, Peter D (2017) Myeloablative hematopoietic stem cell transplantation improves survival but is not curative in a pre-clinical model of myelodysplastic syndrome. PLoS One 12:e0185219
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