The dark side of stemness - the role of hematopoietic stem cells in development of blood malignancies

Abstract

Hematopoietic stem cells (HSCs) produce all blood cells throughout the life of the organism. However, the high self-renewal and longevity of HSCs predispose them to accumulate mutations. The acquired mutations drive preleukemic clonal hematopoiesis, which is frequent among elderly people. The preleukemic state, although often asymptomatic, increases the risk of blood cancers. Nevertheless, the direct role of preleukemic HSCs is well-evidenced in adult myeloid leukemia (AML), while their contribution to other hematopoietic malignancies remains less understood. Here, we review the evidence supporting the role of preleukemic HSCs in different types of blood cancers, as well as present the alternative models of malignant evolution. Finally, we discuss the clinical importance of preleukemic HSCs in choosing the therapeutic strategies and provide the perspective on further studies on biology of preleukemic HSCs.

Keywords: acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; clonal hematopoiesis; hematopoietic stem cell; mature cell neoplasm; preleukemic state.

Figure 1

Classical model of hematopoiesis. HSC, hematopoietic stem cell; MPP, multipotent progenitor; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte-erythrocyte progenitor; GMP, granulocyte-monocyte precursor; MkP, megakaryocyte precursor; ErP, erythrocyte precursor; RBCs, red blood cells; mDC, myeloid dendritic cell.

Figure 2

Possible cellular compartments for the first and final genetic hits. (A–C) HSCs are prone to accumulate preleukemic mutations, due to long lifespan and natural self-renewal properties. Progeny of mutated HSCs inherit the mutations. Final transforming hit may occur at different level of hematopoietic hierarchy: (A) in progenitor cell or (B, C) mature cells. (C) The natural self-renewal of memory B and T cells may further facilitate the accumulation of mutations and complete their malignant transformation. (A–C) The models assume that HSC constitutes the cell-of-origin, and progenitor or mature cell with self-renewal becomes the leukemia stem cell. (D–F) Other models do not ascribe direct role to HSCs in malignant transformation. (D) One possibility is that the early mutation warrants acquired self-renewal to progenitor cells that physiologically do not self-renew. This drives further accumulation of mutations and leads to malignant transformation. (E) Alternatively, the mature self-renewing cells like memory B and T cells may naturally accumulate mutations and constitute the origin of lymphomas or myeloma. (F) Non-self-renewing mature cell is unlikely to become the cell-of-origin of leukemia as mature cells are terminally differentiated. and have to short lifespan to accumulate mutations.

Figure 3

The origin of mutations predisposing to leukemia in newborns. (A) Germline and (B) in utero mutations may trigger preleukemic state and predispose to develop hematologic neoplasm. The disease may appear quickly after birth (e.g., infant ALLs), late in adulthood (e.g. MPNs), or do not occur at all, when no further somatic evolution happens.

Figure 4

Effect of mutation order on leukemogenesis. Type of mutations and their order may determine the phenotype and the kinetics of neoplasm development. (A) The priority of the “landscaping” mutation (TET2) results in domination of TET2 single-mutant cells within HSPC pool. The patients are older at the diagnosis, what indicates that acquisition of secondary/transforming hits requires more time. (B) The first hit in the signaling/proliferative mutation (JAK2) drives expansion of HSPCs pool and majority of these cells are JAK2-TET2 double-mutant. Patients are younger at the diagnosis, indicating shorter time from first hit to overt neoplasm.

Figure 5

Possible mechanisms of relapse in AML after initial treatment and remission. (A) One possibility is that chemotherapy fails to eradicate LSCs that reconstitute the outburst of the leukemic blasts. (B) Alternative model assumes that chemotherapy eradicates the malignant LSCs, but causes new mutation in preleukemic clones, that in turn results in new clones of LSCs and leukemia relapse.

Figure 6

The potential role of lineage-biased HSCs in hematopoietic malignancies. Several studies evidenced the presence of self-renewing subpopulations of HSCs that are multipotent, but show preferential differentiation toward selected lineages, eg. myeloid. The lineage-biased HSCs expand during aging and therefore might be predisposed to accumulate mutations.