Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells

The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of leukemogenesis and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 [CD150(+)CD41(-)CD34(-)Lineage(-)Sca-1(+)c-Kit(+) cells] and HSC2 [CD150(-)CD41(-) CD34(-)Lineage(-)Sca-1(+)c-Kit(+) cells]) and 3 distinct types of HPCs (HPC1 [CD150(+)CD41(+)CD34(-) Lineage(-)Sca-1(+)c-Kit(+) cells], HPC2 [CD150(+)CD41(+)CD34(+)Lineage(-)Sca-1(+)c-Kit(+) cells], and HPC3 [CD150(-)CD41(-)CD34(+)Lineage(-)Sca-1(+)c-Kit(+) cells]) were isolated from adult mouse bone marrow, and examined by competitive repopulation assay. Then, cells from each population were retrovirally transduced to initiate MLL-AF9 acute myelogenous leukemia (AML) and the intracellular domain of NOTCH-1 T-cell acute lymphoblastic leukemia (T-ALL). AML and T-ALL similarly developed from all HSC and HPC populations, suggesting multiple cellular origins of leukemia. New leukemic stem cells (LSCs) were also identified in these AML and T-ALL models. Notably, switching between immunophenotypical immature and mature LSCs was observed, suggesting that heterogeneous LSCs play a role in the expansion and maintenance of leukemia. Based on this mouse model study, we propose that acute leukemia arises from multiple cells of origin independent of the self-renewal and differentiation potentials in hematopoietic stem and progenitor cells and is amplified by LSC switchover.