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.

Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients’ CD34+/CD38− Leukemia Stem Cells

“…After the success of TKIs in extending the lives of CML patients, now the main challenge is elimination of CML cells resistant to TKIs, particularly leukemic stem cells, and reaching treatment-free remission [ 29 , 40 ]. Several therapeutic strategies have been suggested [ 41 , 42 , 43 ], but these investigations are at an early stage.…”

“…Leukemia Stem Cells (LSCs), also named leukemia initiating cells, constitute another BCR-ABL1-independent resistance to TKIs responsible for lack of TFR [ 26 , 27 , 28 , 29 ]. CML LSCs are a population of rare cells with high BCR-ABL1-independent survival skills that initiate leukemia and contribute to its progression and drug resistance.…”

Chronic myeloid leukemia: where do we stand, where can we go?

“…Chronic myeloid leukemia stem cells CML SCs are not fully defined yet in terms of immune and functional characteristics [89]. CML SCs likely share an immunophenotypic profile with normal hematopoietic stem cells (HSCs) and reside in the CD34+/CD38-/Lyn-cell fraction [90].…”

Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells

“…Compared to conventional interferon therapy, these inhibitors have markedly improved the 5‐year survival rate of chronic phase CML patients to more than 90% 5 . However, approximately 30% of patients who receive BCR::ABL1 TKIs develop resistance or intolerance, which is a major clinical problem 6 …”

“…5 However, approximately 30% of patients who receive BCR::ABL1 TKIs develop resistance or intolerance, which is a major clinical problem. 6 A cause of BCR::ABL1 TKI resistance is point mutations in the kinase domain within the BCR::ABL1 protein, which interfere with the binding of BCR::ABL1 TKIs to the BCR::ABL1 protein, thereby reducing the sensitivity of the drug. 7 Currently, there are more than 1000 reported point mutations in the kinase domain of BCR::ABL1.…”