Concise review: preleukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells

Abstract

Recent experimental evidence has shown that acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from transformed immature hematopoietic cells following the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells and committed progenitors. The series of transforming events initially gives rise to preleukemic stem cells (pre-LSC), preceding the formation of fully transformed leukemia stem cells (LSC). Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS. The therapeutic elimination of all LSC, as well as pre-LSC, which provide a silent reservoir for the re-formation of LSC, will be essential for achieving lasting cures. Conventional sequencing and next-generation genome sequencing have allowed us to describe many of the recurrent mutations in the bulk cell populations in AML and MDS, and recent work has also focused on identifying the initial molecular changes contributing to leukemogenesis. Here we review recent and ongoing advances in understanding the roles of pre-LSC, and the aberrations that lead to pre-LSC formation and subsequent LSC transformation.

Figure 1.

Multistep transformation of leukemia stem cells. During healthy hematopoiesis (displayed on the left), HSC give rise to committed progenitor cells that further differentiate into all mature blood cell types. Leukemia arises from hematopoietic cells that have progressively acquired genetic and/or epigenetic modifications (represented by lightning bolt symbols) and ultimately form self-renewing LSC, also known as LIC, that sustain the disease. An initial (“founding”) mutation in HSC or progenitor cells originates the LCO. During the preleukemic stage, the LCO and subsequent preleukemic stem cell stages (pre-LSC) progressively acquire further aberrations and finally generate fully transformed LSC/LIC, which are functionally defined by their ability to initiate disease upon transplantation. These aberrations, illustrated by lightning bolt symbols, include mutations or deregulation of transcription factors, epigenetic factors, metabolic factors, and proteins involved in signal transduction and cell cycle regulation. LSC/LIC are self-renewing and contain a full set of genetic and epigenetic changes that lead to blocked hematopoietic differentiation and the accumulation of dysfunctional leukemic blasts that form the bulk of the tumor cells but are not capable of initiating/maintaining the disease on their own. Abbreviations: HSC, hematopoietic stem cell; LCO, leukemia cell-of-origin; LIC, leukemia-initiating cell; LSC, leukemia stem cell.