We initially used retroviral insertional mutagenesis to identify genes important for leukemic transformation, one of these genes (Erg) has been pursued in collaboration with Dr. Shai Izraeli, and a manuscript describing the results has been recently published. As a complementary approach, we searched for spontaneous (ie, not induced by RIM or gene targeting) mutations that might collaborate with the NHD13 or CALM-AF10 fusions. 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. The genotypes of the leukemias are NHD13, CALM-AF10, NUP98-PHF23, and Lin28b;24 genes commonly mutated in AML and/or T-ALL, including Nras, Kras, Tp53, Notch1, Runx1, Kit, and Flt3 are assayed. We identified spontaneous, acquired mutations in Nras, Kras, Tp53, Notch1, Flt3, Ptpn11, Cbl, and Idh1. Again, in collaboration with Dr. Meltzer, we are analyzing whole-exome deep sequencing 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 gene, not previously implicated in B lineage leukemia. A manuscript describing these findings has been submitted. 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. Stephen Nimer, we have demonstrated a genetic interaction between the NHD13 fusion and p53;this work has recently been published. In collaboration with Dr. David Curtis, we have demonstrated that inhibition of apoptosis by BCL2 prevents leukemic transformation of NHD13 cell;this data has also 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.
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