Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

Abstract

Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These ‘hits’ do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2, associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This ‘hardwiring’ of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.

Zebrafish models of acute leukemias: Current models and future directions

“…It is hypothesized that both AML and ALL arise from genetic alterations that occur in one of the multipotent blood progenitor subtypes (Brown, Sánchez, & Sánchez-García, 2020). Ultimately, this leads to the abnormal proliferation of the progenitor "blast" cells, which interferes with the normal maintenance and production of differentiated blood cells (Figure 1).…”

“…These genetic abnormalities may be passed on by the parents, or may result from multiple genetic mutations acquired throughout the patient's lifetime. Early studies on twins suggested that both AML and ALL require two genetic mutations for progression (Brown et al, 2020).…”

“…Due to the genetic variances in different subtypes, both AML and ALL can be acquired in childhood or adulthood; the nature of the mutation and the time of onset both affect the prognosis of this heterogenous group of cancers. The diverse nature of these different cancers emphasize the necessity for developing more targeted and personalized therapeutic interventions (Brown et al, 2020;L. Long et al, 2020;F.-L. Huang, Liao, Li, Yen, & Yu, 2020;Kirtonia et al, 2020).…”