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 is currently in press. 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 #
1ZIABC010982-10
Application #
9556417
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Goldberg, Liat; Gough, Sheryl M; Lee, Fan et al. (2017) Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance. Genes Chromosomes Cancer 56:472-483
Bhagat, Tushar D; Chen, Si; Bartenstein, Matthias et al. (2017) Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/?-Catenin Activation. Cancer Res 77:4846-4857
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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
Bailey, Emily J; Duffield, Amy S; Greenblatt, Sarah M et al. (2013) Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication mutation. Comp Med 63:218-26
Levens, David; Aplan, Peter D (2013) Notching up MYC gives a LIC. Cell Stem Cell 13:8-9

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