Activation of Proto-Oncogenes by Chromosomal Translocation

Division Of Clinical Sciences - Nci

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Abstract

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 acute lymphocytic leukemia patients; a preliminary survey suggest that patients with CRLF2 overexpression preferentially utilize V regions used in B1 lymphocytes, suggesting that these B cell precursor acute lymphocytic leukemia may be derived from B1 progenitors. Finally, whole exome sequence (WES) analysis of these leukemias revealed that all have mutations involving Bcor and Jak/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. Manuscripts describing these findings and the utility of this model for pre-clinical studies were published in FY 2018-2020. Ongoing studies are focused on using these in vivo models to inform clinical trials of B-cell precursor acute lymphocytic leukemia. In addition, a manuscript describing the molecular basis for NP23 oncogenic effects was published in FY2020. 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 acute myeloid leukemia. 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 and several offspring have developed hematologic malignancy. A large series of pediatric acute myeloid leukemia 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 acute myeloid leukemia. Unexpectedly, acute myeloid leukemia is not increased in the F1 generation; we have recently generated another group of founder mice: one of these has developed acute myeloid leukemia 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. A portion of these results were published in FY2021. Leukemia (predominantly acute myelocytic leukemia and acute lymphocytic leukemia) is the most common malignancy in children. The results of these studies are relevant for improving our understanding of childhood cancer, and have led to new diagnostics (the SIL-TAL1 fusion) and generated mouse models that can be used for pre-clinical studies.