We previously identified mutations of candidate genes including Flt3, Nras, Kras, Ptpn11, and Cbl. More recently, in collaboration with Dr. Paul Meltzer, we have used multiplex PCR and deep sequencing to identify mutations in 24 candidate genes in a set of 152 mouse leukemias and identified spontaneous, acquired mutations in Nras, Kras, Tp53, Notch1, Flt3, Ptpn11, Cbl, and Idh1; a manuscript describing these findings is in preparation. Again, in collaboration with Dr. Meltzer, we analyzed whole-exome deep sequence of the leukemias that develop in NUP98-PHF23 (NP23) mice and the PTCL that developed in Lin28b mice. Unexpectedly, we identified frequent mutations in progenitor B1 cell ALL in the Bcor and Jak1/2 genes. A manuscript describing these findings has been reviewed and is being revised. Furthermore, we have used CRISPR to introduce Bcor mutations in primary WT and NP23 BM cells; these cells have been transplanted into recipient mice to determine if we can verify collaboration between NP23 and Bcor in vivo. Additional in vivo genetic crosses, performed in collaboration with Dr. Donald Small and Dr. Trang Hoang have demonstrated that the NHD13 transgene can collaborate with a Flt3 ITD to induce a myeloid leukemia, and there is an in vivo interaction between SCL and c-Kit that is important for early hematopoietic differentiation. A manuscript describing the Flt3 and NHD13 interaction, as well as its potential clinical relevance, has recently been published. As mentioned above, spontaneous mutations of IDH2 were identified in NHD13 leukemias. These mutations occur at R140Q; homologous residues are mutated in human leukemia. We crossed IDH2 R140Q transgenic mice with NHD13 mice; the offspring develop a form of early T cell precursor (ETP) leukemia that resembles the human disease in terms of clinical presentation, immunophenotype, gene expression profile, and collaborative mutations. A manuscript describing these findings is in preparation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010982-09
Application #
9343760
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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