We generated mice that expressed a NUP98-PHF23 (NP23) fusion in hematopoietic cells. Almost 100% of these mice develop leukemia within 1 year of life; the leukemic phenotype is very broad, including T and B cell leukemias, myeloid leukemias, and erythroid leukemias. A subset of NP23 mice developed a leukemia of B1 progenitor origin. These leukemias had a B1 progenitor immunophenotype and preferential usage of V regions utilized by B1 lymphocytes. Similar to normal B1 progenitors, these pro B1 leukemias express CRLF2, a subunit for the TSLP receptor. Interestingly, CRLF2 is overexpressed due to chromosomal rearrangement in over 10% of B cell precursor ALL patients; a preliminary survey suggest that patients with CRLF2 overexpression preferentially utilize V regions used in B1 lymphocytes, suggesting that these B cell precursor ALL may be derived from B1 progenitors. Finally, whole exome sequence (WES) analysis of these leukemias revealed that all have mutations involving Bcor and Jake/Stat pathway genes, suggesting a genetic mechanism for this disease. The NP23 fusion leads to stem cell self renewal, the Bcor mutation blocks B cell differentiation, and the Jak/Stat mutation leads to hyperproliferation. A manuscript describing these findings was published in FY 2018, and a second manuscript, which demonstrates that CRISPR-mediated Bcor frameshift mutations collaborates with the NP23 transgene in vivo is currently under review. NP23 leukemias consistently overexpress a novel gene designated Bahcc1 (for Bromo Adjacent Homology Domain And Coiled-Coil Containing 1). Publicly available expression data indicates that BAHCC1 is overexpressed in several distinct subsets of AML. We have generated transgenic mice that overexpress the Bahcc1 gene in hematopoietic cells, and are currently studying hematopoietic development and leukemic transformation in these mice. A large series of pediatric AML patients has demonstrated that over 5% of patients have a NUUP98-NSD1 fusion, and that this fusion predicts a poor response to chemotherapy. We have cloned a NUP98-NSD1 fusion into the Vav1 expression vector, and generated mice that have incorporated the transgene. Several of the founders have developed AML, and we are currently studying a cohort of offspring to determine the penetrance of AML in these mice. Finally, in collaboration with Dr. Munira Basrai of the Genetics branch, we have generated mice that overexpress CENPA in the hematopoietic compartment. CENPA overexpression in yeast and cultured cell lines leads to chromosomal mis-segregation; the transgenic mice will enable us to determine if the mis-segregation takes place in primary cells as well. Moreover, CENPA overexpression has been linked to several malignancies, these mice will enable us to determine if CENPA overexpression is oncogenic in vivo.
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