Multiple cells of origin in common with various types of mouse N-Myc acute leukemia

Little is known regarding whether the cell of origin differs among different leukemia types. To address this fundamental issue, we determined the cell of origin in five distinct types of acute leukemia induced by N-Myc overexpression in mice. CD150⁺CD48^-CD41^-CD34^-c-Kit⁺Sca-1⁺Lin^- (KSL) (HSC1) cells, CD150^-CD48^-CD41^-CD34^-KSL (HSC2) cells, CD150⁺CD41⁺CD34^-KSL (HPC1) cells, CD150⁺CD41⁺CD34⁺KSL (HPC2) cells, and CD150^-CD41^-CD34⁺KSL (HPC3) cells were purified from the bone marrow of adult C57BL/6 mice, transduced with the N-Myc retrovirus vector, and transplanted into lethally irradiated mice. B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), acute undifferentiated leukemia (AUL), and mixed phenotype acute leukemia (MPAL) developed from five populations. RNA sequencing data supported the phenotypical diagnoses of leukemia, except that AUL appeared transcriptionally close to T-ALL. Whole-genome sequencing revealed that retroviral integration sites were irrelevant to the leukemia types and that T-ALL and AML of MPAL shared the same integration site and many gene mutations, suggesting their common origin. Additionally, leukemic stem cells were identified in the KSL cell population, suggesting that the phenotypes of leukemic stem cells are irrelevant to leukemia types. This study provides experimental evidence for the similar and multiple cells of origin in acute leukemia.