Druggable Biochemical Pathways and Potential Therapeutic Alternatives to Target Leukemic Stem Cells and Eliminate the Residual Disease in Chronic Myeloid Leukemia

Abstract

Chronic Myeloid Leukemia (CML) is a disease arising in stem cells expressing the BCR-ABL oncogenic tyrosine kinase that transforms one Hematopoietic stem/progenitor Cell into a Leukemic Stem Cell (LSC) at the origin of differentiated and proliferating leukemic cells in the bone marrow (BM). CML-LSCs are recognized as being responsible for resistances and relapses that occur despite the advent of BCR-ABL-targeting therapies with Tyrosine Kinase Inhibitors (TKIs). LSCs share a lot of functional properties with Hematopoietic Stem Cells (HSCs) although some phenotypical and functional differences have been described during the last two decades. Subverted mechanisms affecting epigenetic processes, apoptosis, autophagy and more recently metabolism and immunology in the bone marrow microenvironment (BMM) have been reported. The aim of this review is to bring together the modifications and molecular mechanisms that are known to account for TKI resistance in primary CML-LSCs and to focus on the potential solutions that can circumvent these resistances, in particular those that have been, or will be tested in clinical trials.

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

“…EPHB4 appears to be one element of the resistance of CML cells to imatinib in a cellular model that consists in two cell lines established from the diagnostic and relapse stages of a unique patient [92]. Interestingly, in 2012, HHT/omacetaxine was shown to be a safe and effective alternative treatment in a phase 2 study on 62 CML patients bearing the T315I BCR-ABL mutation [93], which is associated with resistance to all clinically available TKIs [94].…”

CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies

“…However, the accelerated and blast phases of the disease remain high-risk categories, possibly to the limited activity of tyrosine kinase inhibitors against CD34+/CD38− leukemic stem cells. Therefore, multiple studies are being conducted to identify new therapeutic agents targeting CML stem cells [ 47 ]. The expression of CD123 was found on CD34+/CD38− cells in CML patients, and the level of expression increased with disease progression [ 48 ].…”

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

“…The mechanisms of CML LSC self-renewal and survival are regulated by diverse pathways that can depend on the signaling pathways activated by BCR-ABL1 (reviewed in refs. [11][12][13] ). Many factors in the bone marrow microenvironment that provide signals to CML LSCs for homing and survival (e.g., SDF1, FGF2, IL-8, WNT, miRNA, TGF-β, and STAT3/5) have been described, while immune cells, such as regulatory T cells, myeloidderived suppressor cells (MDSCs), T cells, and-most importantly-natural killer (NK) cells, prevent disease progression and patrol residual LSCs in patients on TKI therapy (Fig.…”

“…2). Figure 2 depicts a simplified view of the main mechanisms involved in LSC maintenance, which have been reviewed in excellent articles [11][12][13] . These mechanisms promote LSC survival via cytokines and growth factors within the bone marrow microenvironment.…”