Chronic Myeloid Leukemia Stem Cells

Abstract

Although rare, chronic myeloid leukemia (CML) represents an important paradigm for understanding the molecular events leading to malignant transformation of primitive hematopoietic progenitors. CML was the first cancer to be associated with a defined genetic abnormality, BCR-ABL, that is necessary and sufficient for initiating chronic phase disease as well as the first cancer to be treated with molecular targeted therapy. Malignant progenitors or leukemia stem cells (LSCs) evolve as a result of both epigenetic and genetic events that alter hematopoietic progenitor differentiation, proliferation, survival, and self-renewal. LSCs are rare and divide less frequently, and thus, represent a reservoir for relapse and resistance to a molecularly targeted single agent. On subverting developmental processes normally responsible for maintaining robust life-long hematopoiesis, the LSCs are able to evade the majority of current cancer treatments that target rapidly dividing cells. Enthusiasm for the enormous success of tyrosine kinase inhibitors at controlling the chronic phase disease is tempered somewhat by the persistence of the LSC pool in the majority of the patients. Combined therapies targeting aberrant properties of LSC may obviate therapeutic resistance and relapse in advanced phase and therapeutically recalcitrant CML.

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

“…The differences observed between CML patients and normal donors during differentiation from CMP to MEP or GMP were modest, reflecting the lack of a differentiation block in CP CML. 15 Analyzing the overlap of genes regulated during transition from HSC to CMP in CML patients and normal donors, we found only six genes concordantly regulated (Supplementary Figure 3). A pathway analysis of the differentially expressed genes showed a significant regulation of cell differentiation related genes during transition from HSC to CMP only in normal donors (27/572 annotated genes, P ¼ 0.006283) and not in CML patients.…”

Migration rules: tumours are conglomerates of self-metastases

“…The rest are able to divide only a certain number of times before they deplete their generational capacity. Supporting the theory, small cancer stem cell populations are strongly implicated in leukaemia (Furth and Kahn, 1937;Kavalerchik et al, 2008) and tumour-initiating side populations have also recently been identified in solid tumours of the breast, colon and prostate, for example (Al-Hajj et al, 2003;Boman and Huang, 2008;Kakarala and Wicha, 2008;Maitland and Collins, 2008;Price et al, 2008). Taking these basic population-level features into account, we designed an agent-based computer model of cancer cell dynamics operative throughout tumour development (see Anderson et al (2007) and Deutsch and Dormann, (2005) for similar approaches).…”

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

“…In CML, the Ph chromosome is believed to originate in a hematopoietic stem cell (HSC) as it clonally can be found both in myeloid and lymphoid cells (5). CML consists of heterogeneous cell types at various maturation stages that are maintained by a small number of cells, termed CML stem cells, sharing with normal HSCs the capacity to self-renew (6). The CML stem cells are at least partially resistant to current treatments with tyrosine kinase inhibitors (TKIs) (7,8) that, despite clinical success, show a suppressive rather than curative effect in this disease.…”