Abstract 3098: Myc preferentially transforms hematopoietic stem cells into Precursor B cell lymphoblastic leukemia/lymphoma

Abstract Overexpression of Myc oncogenes (c-Myc, N-Myc and L-Myc) is frequently found in a wide range of tumors. Although many reports have shown that Myc can directly induce tumors in mice models, the cell-of-origin of the Myc-induced tumor is still unclear. In this study, we attempted to determine the cell-of-origin in the Myc-induced hematopoietic tumor by using bone marrow transplantation model. Bone marrow (BM) cells were harvested from 5FU-treated mice (6 to 8-week-old C57BL/6 mice) and then infected with retroviral vectors to express one of Myc genes, N-Myc. The infected cells were intravenously transplanted into irradiated syngenic mice. As a result, all mice transplanted with N-Myc-transduced BM cells died around 2 months. Those mice showed enlarged lymph nodes, splenomegaly and invaded livers. Abnormally increased WBCs in those mice showed B220+CD19+CD43+/−IgM−, indicating that enhanced expression of N-Myc in BM cells caused Precursor B cell lymphoblastic leukemia/lymphoma (Pre-B LBL). To determine the cell-of-origin of this tumor, the N-Myc-transduced BM cells were fractionated into hematopoietic stem cells (HSCs), committed lymphoid progenitors (CLPs) or myeloid progenitors (MPs) by cell sorter, and those fractions were transplanted into irradiated recipients. Limiting dilution analysis revealed that mice transplanted with HSCs had Pre-B LBL at significant higher frequencies (1:184) than mice transplanted with CLPs (1:558) or MPs (1:9286). Furthermore, to determine whether more lineage-committed cells can be directly the cell of origin, we sorted immature-B cells transduced with N-Myc from non-treated BM cells and transplanted those cells into recipients. While we could not obtain any tumors from those transplanted mice, mice transplanted with immature-B (B220+CD19+IgD−IgM−) cells derived from p16Ink4a−/−p19Arf−/− mice had Pre-B LBL, suggesting that committed B cells could be the direct cell-of-origin in the absence of p16Ink4a and p19Arf genes which are known as tumor suppressor genes. Lastly, we confirmed that another Myc family gene c-Myc also could induce Pre-B LBL, showing similar histopathology and immunophenotype to the N-Myc-induced pre-B LBL. Collectively, our findings indicate that Myc genes can preferentially transform HSCs into Pre-B LBL and, that p16Ink4a and p19Arf genes can be crucial barriers to block Myc-induced oncogenic stress in more committed cells than HSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3098.