BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia

Abstract

Not all chronic myeloid leukemia (CML) patients are cured with tyrosine kinase inhibitors (TKIs), and a proportion of them develop resistance. Recently, continuous BCR-ABL gene expression has been found in resistant cells with undetectable BCR-ABL protein expression, indicating that resistance may occur through kinase independent mechanisms, mainly due to the persistence of leukemia stem cells (LSCs). LSCs reside in the bone marrow niche in a quiescent state, and are characterized by a high heterogeneity in genetic, epigenetic, and transcriptional mechanisms. New approaches based on single cell genomics have offered the opportunity to identify distinct subpopulations of LSCs at diagnosis and during treatment. In the one hand, TKIs are not able to efficiently kill CML-LSCs, but they may be responsible for the modification of some LSCs characteristics, thus contributing to heterogeneity within the tumor. In the other hand, the bone marrow niche is responsible for the interactions between surrounding stromal cells and LSCs, resulting in the generation of specific signals which could favor LSCs cell cycle arrest and allow them to persist during treatment with TKIs. Additionally, LSCs may themselves alter the niche by expressing various costimulatory molecules and secreting suppressive cytokines, able to target metabolic pathways, create an anti-apoptotic environment, and alter immune system functions. Accordingly, the production of an immunosuppressant milieu may facilitate tumor escape from immune surveillance and induce chemo-resistance. In this review we will focus on BCR-ABL-independent mechanisms, analyzing especially those with a potential clinical impact in the management of CML patients.

Long-Term Remission Achieved by Ponatinib and Donor Lymphocytes Infusion in a Ph+ Acute Lymphoblastic Leukemia Patient in Molecular Relapse After Allogenic Stem Cell Transplant and Dasatinib: A Case Report

“…Accordingly, we quickly achieved a molecular response with no signs of acute GVHD other than a manageable cutaneous dyskeratosis, and the patients received 5 consecutive DLI injections, continuing to maintain a complete molecular response. Interestingly, the treatment combination produced several immune changes within the BM, that are in line with the reported immunomodulatory activity of this class of drugs (18,19). We indeed observed a "normalization" in bone marrow composition (including a repopulation in precursor and naïve b and T cells) coupled with an unbalance in the CD8/CD4 ratio in favor of the cytotoxic CD8 T cell population, known to be essential for anticancer response (20).…”

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

“…Mutations in drug-targeted proteins lead to changes in protein conformation and insensitivity to anticancer drugs of tumor cells [160]. It has been reported that tyrosine kinase inhibitors are effective to treat chronic myeloid leukemia (CML) by targeting the BCR-ABL protein in CML cells [161,162]. However, the development of drug resistance in patients during treatment is mainly caused by a mutation in the BCR-ABL protein [163,164].…”

HDAC6—An Emerging Target Against Chronic Myeloid Leukemia?

“…These allow interactions between the LSCs and the cells of the microenvironment, which can promote the development of resistance mechanisms. The persistence of LSCs in the presence of TKIs could be the cause of the molecular minimal residual disease that can promote the long-term development of resistance, making them potentially responsible for the clonal evolution and progression of CML [71].…”