N-MYC INDUCES VARIOUS TYPES OF MOUSE ACUTE LEUKEMIA

N-Myc plays a role in the regulation of proliferation, differentiation, and survival of hematopoietic stem cells (HSCs) and leukemogenesis. We studied the cell of origin in the mouse acute leukemia model by N-Myc-overexpression. Our single cell RNA-seq data showed that N-Myc is restrictively expressed in HSCs and hematopoietic progenitor cells (HPCs) whereas c-Myc, but not L-Myc, is widely expressed in a variety of hematopoietic cells. HSC1, HSC2, HPC1, HPC2, and HPC3 with different self-renewal and differentiation potentials were isolated from the bone marrow of adult B6 mice. These cells were retrovirally overexpressed with N-Myc and transplanted into lethally irradiated mice with competitor cells. Acute leukemia developed from all these populations. Notably, not only B cell acute lymphoid leukemia (B-ALL), but also T cell ALL (T-ALL), acute myeloid leukemia (AML), acute undifferentiated leukemia (AUL), and mixed phenotype acute leukemia (MPAL) developed. Metascape analysis of RNA-seq data showed that RNA profiles each from B-ALL, T-ALL, AML and AUL samples were enriched in special cellular signaling pathways. Collectively, the multiple cells of origin suggested that the self-renewal and differentiation potentials of cells were not related to leukemogenesis induced by N-Myc-overexpression. In addition, whole genome sequencing data suggested that retroviral integration sites play a role in the development of different types of leukemia.