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 was published in FY 2019. 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. Preliminary studies have demonstrated that two of the founder mice have developed hematologic malignancy. A large series of pediatric AML patients has demonstrated that over 5% of patients have a NUP98-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. Three of the founders developed AML. Unexpectedly, AML is not increased in the F1 generation; we have recently generated another group of founder mice: one of these has developed AML thus far, and we are studying F1 offspring of this founder. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC010378-19
Application #
10015013
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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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Maegawa, Shinji; Gough, Sheryl M; Watanabe-Okochi, Naoko et al. (2014) Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res 24:580-91

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