Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

Abstract

Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self‐renewal, such as Wnt/β‐catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018;7:305–314

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

“…This is the first study to provide functional ground for investigating the role for USP15 as gatekeeper in leukemia. Our in vitro assays support targeting USP15 to suppress viability of a subset of leukemia cell lines, including cell lines derived from blast crisis stage CML, a stem-cell derived disease (Arrigoni et al, 2018). In both normal and tumor cells, USP15 inhibition is accompanied by chromosomal aberrations indicating a susceptibility to DNA damage.…”

Separase activity distribution can be a marker of major molecular response and proliferation of CD34+ cells in TKI-treated chronic myeloid leukemia patients

“…It is assumed that TKI treatment reduces turnover and self-renewal of BCR-ABL1-positive LSCs but also facilitates a "low mutator" phenotype. Namely, LSCs neither exhibit mutation-driven TKI resistance nor progress to advanced phase but keep acquiring increased levels of radical oxygen species (ROS) and are supposed to activate other mechanisms preparing the ground for later clonal evolution and tumor progression [11,12].…”

“…Since only few factors for leukemic stem cell (LSC) dormance are identified so far, it is important to explore new targets and to develop potent small molecules for eradication of the leukemia clone [11][12][13].…”

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

“…These pathways are also involved in the resistance to apoptosis in CML cells and are associated with imatinib resistance in CML patients (Danisz & Blasiak, ). Pathway enrichment involves cytokine‐cytokine receptor pathways, including tyrosine kinase receptor activity and phosphokinase receptor and androgen receptor pathway activation; TKIs are currently the primary treatment for CML patients (Arrigoni et al, ). Notch signaling is critical for HSC self‐renewal and survival.…”