Is lineage decision-making restricted during tumoral reprograming of haematopoietic stem cells?

Abstract

Within the past years there have been substantial changes to our understanding of haematopoiesis and cells that initiate and sustain leukemia. Recent studies have revealed that developing haematopoietic stem and progenitor cells are much more heterogeneous and versatile than has been previously thought. This versatility includes cells using more than one route to a fate and cells having progressed some way towards a cell type retaining other lineage options as clandestine. These notions impact substantially on our understanding of the origin and nature of leukemia. An important question is whether leukemia stem cells are as versatile as their cell of origin as an abundance of cells belonging to a lineage is often a feature of overt leukemia. In this regard, we examine the coming of age of the “leukemia stem cell” theory and the notion that leukemia, like normal haematopoiesis, is a hierarchically organized tissue. We examine evidence to support the notion that whilst cells that initiate leukemia have multi-lineage potential, leukemia stem cells are reprogrammed by further oncogenic insults to restrict their lineage decision-making. Accordingly, evolution of a sub-clone of lineage-restricted malignant cells is a key feature of overt leukemia.

The changing face of hematopoiesis: a spectrum of options is available to stem cells

“…However, it has been clear for many years that the bulk of cells of each leukemia belong to just one cell lineage, and leukemias are categorized accordingly. Similarly, molecular and genetic analyses have shown associations between a certain genetic lesion and a particular subtype of leukemia, and of other cancers (reviewed in Brown and Sanchez‐Garcia). Hence, there is an intimate association between a genotypic lesion and phenotype, and, as above, the cell lineage nature of the leukemia cells.…”

Modeling the Hematopoietic Landscape

“…Sánchez-Garcia and colleagues have argued that restriction of a leukemic HSC to one pathway occurs by oncogenes orchestrating the epigenome toward a leukemic cell lineage – with additional oncogene insults then converting this cell into a leukemia stem cell (LSC). Activity of the first oncogene is neither necessary to maintain LSCs nor for disease progression (Brown and Sanchez-Garcia, 2015; García-Ramírez et al, 2018; Vicente-Dueñas et al, 2018; Vicente-Dueñas et al, 2019). Its role is to focus HSC options into only one pathway, thus restricting LSCs and their progeny to that pathway.…”

Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

“…Given the above evidence, the first oncogenic insult to a tissue-specific stem cell initiates carcinogenesis by restricting lineage choices of LSCs and other CSCs, and directing their progeny into a single developmental pathway [30,58]. In this scenario, LSCs/CSCs and their progeny lack the versatility of HSCs/HPCs, which is an essential difference between normal and cancer stem cells.…”