We searched for spontaneous mutations that might collaborate with the NHD13, CALM-AF10, NP23 fusions or Lin28b overexpression. We identified mutations of candidate genes including Flt3, Nras, Kras, Ptpn11, and Cbl, and published this data in 2012. 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. We 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 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 is currently in the review process. In addition, we have identified spontaneous mutations in a number of chromatin modifying genes in the mice with PTCL. The identification of spontaneous mutations in genes known to promote leukemic transformation supports the contention that these animal models faithfully recapitulate the human disease, while the identification of novel genes suggests previously unsuspected genes and pathways important for specific subtypes of leukemia and lymphoma. In collaboration with Dr. Linda Wolff, we identified a genetic interaction between p15 and NHD13; this work has recently been published. 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 fo rearly hematopoietic differentiation. As mentioned above, studies involving NHD13 and mutant IDH2 co-expression are currently in progress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010982-08
Application #
9153735
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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Gough, Sheryl M; Lee, Fan; Yang, Fan et al. (2014) NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer Discov 4:564-77
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Levens, David; Aplan, Peter D (2013) Notching up MYC gives a LIC. Cell Stem Cell 13:8-9

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