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

Abstract

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.

Lineage marker expression on mouse hematopoietic stem cells

“…HPC1 was enriched in myeloid HPCs. HPC2 was enriched in day 12 colony-forming cells in spleen, and HPC3 was enriched in lymphoid-primed multipotent progenitors [15,18,20,21]. The relationship between Trampp's classification and our classification has previously been reported [21].…”

“…HPC2 was enriched in day 12 colony-forming cells in spleen, and HPC3 was enriched in lymphoid-primed multipotent progenitors [15,18,20,21]. The relationship between Trampp's classification and our classification has previously been reported [21]. We used a lineage antibody cocktail consisting of seven lineage antibodies (see Methods) in this experiment.…”

The invasion of de-differentiating cancer cells into hierarchical tissues

“…Perhaps an example of the differences between stepwise and jumpwise de-differentiation and the implications of the subsequent disease behavior can be illustrated by various types of leukemia. As already mentioned, MLL-AF9 expression in committed progenitor cells can lead to the development of leukemic stem cells that can result in disease transmission across mice [27, 58]. In general MLL expression is associated with a poor prognosis in acute myeloid leukemia [59, 60].…”

The invasion of de-differentiating cancer cells into hierarchical tissues

“…Perhaps an example of the differences between stepwise and jumpwise de-differentiation and the implications of the subsequent disease behavior can be illustrated by various types of leukemia. As already mentioned, MLL-AF9 expression in a committed progenitor cells can lead to the development of leukemic stem cells that can result in disease transmission across mice [27,46]. In general MLL expression is associated with a poor prognosis in acute myeloid leukemia [47,48].…”