Targeting stem cells in myelodysplastic syndromes and acute myeloid leukemia

Abstract

The genetic architecture of cancer has been delineated through advances in high-throughput next-generation sequencing, where the sequential acquisition of recurrent driver mutations initially targeted towards normal cells ultimately leads to malignant transformation. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies frequently initiated by mutations in the normal hematopoietic stem cell compartment leading to the establishment of leukemic stem cells. Although the genetic characterization of MDS and AML has led to identification of new therapeutic targets and development of new promising therapeutic strategies, disease progression, relapse, and treatment-related mortality remain a major challenge in MDS and AML. The selective persistence of rare leukemic stem cells following therapy-induced remission implies unique resistance mechanisms of leukemic stem cells towards conventional therapeutic strategies and that leukemic stem cells represent the cellular origin of relapse. Therefore, targeted surveillance of leukemic stem cells following therapy should, in the future, allow better prediction of relapse and disease progression, but is currently challenged by our restricted ability to distinguish leukemic stem cells from other leukemic cells and residual normal cells. To advance current and new clinical strategies for the treatment of MDS and AML, there is a need to improve our understanding and characterization of MDS and AML stem cells at the cellular, molecular, and genetic levels. Such work has already led to the identification of promising new candidate leukemic stem cell molecular targets that can now be exploited in preclinical and clinical therapeutic strategies, towards more efficient and specific elimination of leukemic stem cells.

Keywords: acute myeloid leukemia; clonal evolution; hematopoietic stem cells; leukemic stem cells; myelodysplastic syndromes; therapeutic targets.

Fig. 1

Clonal evolution within distinct hematopoietic stem and progenitor cell compartments. Normal hematopoietic stem cells (HSCs) do not have any detectable driver mutations. In clonal hematopoiesis (CH), a recurrent driver mutation is acquired. Findings suggest that to be sustained in the long term the CH mutation must be targeted to HSCs possessing extensive self‐renewal potential. In low‐to‐intermediate‐risk myelodysplastic syndromes (MDS), additional driver mutations are acquired, and these must also typically be targeted to normal or CH stem cells to be sustained over time, as these mutations will not introduce the self‐renewal ability to downstream progenitors. In contrast, in progressed high‐risk MDS and transformed acute myeloid leukemia (AML), long‐term self‐renewal potential also appears to have been acquired by downstream progenitors, and therefore new mutations might initially have been targeted towards a progenitor rather than an HSC.

Fig. 2

Current common therapeutic approaches for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The treatment of MDS and AML depends on patient and disease characteristics. Under supportive treatment (a), normal hematopoietic functions can be improved without significantly reducing the leukemic burden by infusion of mature blood cells (red blood cells, platelets) or stimulation of hematopoietic differentiation by cytokines such as EPO, G‐CSF, or TPO‐mimetics. Clone reductive treatment (b) allows for reduction of the leukemic burden, either by preferential elimination of clonally involved cells or targeting of both normal and leukemic cells. Following transplantation (c), endogenous normal and leukemic cells are replaced by normal donor‐derived hematopoietic cells.

Fig. 3

Genetic and cellular prediction of relapse. (a) Genetic composition of the malignant clone at diagnosis (Dx) and relapse where relapse is composed of the same dominant clone found at diagnosis (left), relapse originates from the clone dominating at diagnosis but with acquisition of a new genetic lesion (middle), and relapse originating from a clone not detected at diagnosis (right). (b) Treatment resulting in remission and subsequent relapse where relapse originates from a selectively persistent leukemic stem cell population at remission. The graphs illustrate the enhanced sensitivity of minimal residual disease (MRD) detection through targeted stem/progenitor cell analysis at remission.

Fig. 4

Exploiting cell surface and somatic genetic lesions for targeting of myelodysplastic syndrome– and/or acute myeloid leukemia–propagating cells. Genetic alterations in the form of DNA mutations or chromosome changes can allow the development of cellular and molecular therapeutics aimed specifically towards clonally involved cells. Leukemic cells can also acquire altered expression of normal cell surface molecules, which can be exploited therapeutically to activate complement‐dependent cytotoxicity (CDC), antibody‐dependent cellular cytotoxicity (ADCC), or antibody‐dependent cellular phagocytosis (ADCP), or be targeted by antigen‐specific T cells.