Preleukemic Hematopoietic Stem Cells in Human Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by an uncontrolled proliferation of undifferentiated myeloid lineage cells. Decades of research have demonstrated that AML evolves from the sequential acquisition of genetic alterations within a single lineage of hematopoietic cells. More recently, the advent of high-throughput sequencing has enabled the identification of a premalignant phase of AML termed preleukemia. Multiple studies have demonstrated that AML can arise from the accumulation of mutations within hematopoietic stem cells (HSCs). These HSCs have been termed "preleukemic HSCs" as they represent the evolutionary ancestors of the leukemia. Through examination of the biological and clinical characteristics of these preleukemic HSCs, this review aims to shed light on some of the unexplored questions in the field. We note that some of the material discussed is speculative in nature and is presented in order to motivate future work.

Keywords: acute; clonal evolution; clonal hematopoiesis; leukemia; myeloid; preleukemic hematopoietic stem cell; premalignant lesions.

Figure 1

Preleukemic burden is highly variable in acute myeloid leukemia (AML) patients. (A) Preleukemic burden is defined as the percentage of hematopoietic stem cells (HSCs) in an AML patient that harbor at least the earliest preleukemic mutation. This diagram depicts the preleukemic phase of evolution with the acquisition of three distinct mutations represented by three distinct colors (blue, orange, and purple). Eventually, the first mutation (blue) is present in every HSC, leading to a preleukemic burden of 100%. (B) This diagram depicts the acquisition of the same three mutations shown in panel (A) but the resulting HSCs fail to expand. In this scenario, only a minority of the HSCs harbor mutations, and therefore, the preleukemic burden is low.

Figure 2

Treatment scenarios in acute myeloid leukemia (AML) and the impact of preleukemic hematopoietic stem cells (HSCs). (A) The ideal treatment would combine a therapy targeted against the frankly leukemic cells (such as anti-FLT3 therapy) to eradicate AML cells followed by a targeted therapy against the preleukemic cells (such as anti-DNMT3A therapy). This would lead to long-term durable remission and disease cure. (B) Current AML therapies largely target late mutations, such as FLT3-ITD, which are not present in preleukemic HSCs. In the event that all AML cells are eradicated, the preleukemic HSCs could eventually lead to relapsed disease. (C) Targeting of preleukemic HSCs in the context of high preleukemic burden could lead to bone marrow failure and cytopenias as the vast majority of HSCs would be targeted.

Figure 3

Targeted treatment of preleukemic mutations may be context dependent. In chronic phase CML, treatment with imatinib efficiently targets heamtopoietic progenitor cells (HPCs) but does not target HSCs, likely due to context specificity.