Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia

Abstract

Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient's long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.

Keywords: chronic myeloid leukemia; leukemia stem cell; metabolic regulation; microenvironment.

Figure 1

CML leukemic stem cells, and c of the bone marrow microenvironment for CML LSCs. CD26 disrupts the CXCL12/CXCR4 axis by cleaving CXCL12 to promote LSCs’ mobilization into the blood. LSCs bind to VCAM-1 and Selectin on their bone marrow niche. Secretion of LSCs demand a tightly regulated metabolism. BMP2/4 and other chemokines/cytokines through auto- or paracrine mechanisms also support quiescence, cellular growth, and drug resistance of CML LSCs. LSC, leukemia stem cell; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late antigen 4; CXCL12, C-X-C motif chemokine 12; SCF, stem cell factor; BMP, bone morphogenetic protein.