Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review.

Mohammad Al Hamad

doi:10.12688/f1000research.74570.1

Mohammad Al Hamad

Open Access

https://doi.org/10.12688/f1000research.74570.1

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Journal: F1000Research	Publication Date: Dec 15, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Imam Abdulrahman Bin Faisal University

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm generated by reciprocal chromosomal translocation, t (9; 22) (q34; q11) in the transformed hematopoietic stem cell. Tyrosine kinase inhibitors (TKIs) target the mature proliferating BCR-ABL cells, the major CML driver, and increase overall and disease-free survival. However, mutant clones, pre-existing or due to therapy, develop resistance against TKIs. BCR-ABL1 oncoprotein activates various molecular pathways including the RAS/RAF/MEK/ERK pathway, JAK2/STAT pathway, and PI3K/AKT/mTOR pathway. Stimulation of these pathways in TKI resistant CML patients, make them a new target. Moreover, a small proportion of CML cells, leukemic stem cells (LSCs), persist during the TKI therapy and sustain the disease in the patient. Engraftment of LSCs in the bone marrow niche and dysregulation of miRNA participate greatly in the TKI resistance. Current efforts are needed for determining the reason behind TKI resistance, identification, and elimination of CML LSC might be of great need for cancer cure.

Highlights

The BCR-ABL gene results from a reciprocal translocation t (9; 22) (q34; q11) in the transformed hematopoietic stem cell (HSC).[1,2,3] BCR-ABL is considered the most common genetic abnormality in chronic myeloid leukemia (CML) (95%), followed by acute lymphocytic leukemia (ALL) (35%), and rarely presented in acute myelogenous leukemia (AML) (1%).[4,5,6] The most detected variant of BCR-ABL in CML is P210 BCR-ABL1 that occasionally presents in ALL and AML
The P210 BCR-ABL1 variant expresses in about 48% of Ph+ CML cases, while 52% co-express P210 BCR-ABL1 and P190 BCR-ABL1 variants.[7]
The cryptic Ph chromosome can be detected by fluorescence in situ hybridization (FISH) and/or real-time polymerase chain reaction (PCR).[9]

Summary

Introduction

The BCR-ABL gene results from a reciprocal translocation t (9; 22) (q34; q11) in the transformed hematopoietic stem cell (HSC).[1,2,3] BCR-ABL is considered the most common genetic abnormality in chronic myeloid leukemia (CML) (95%), followed by acute lymphocytic leukemia (ALL) (35%), and rarely presented in acute myelogenous leukemia (AML) (1%).[4,5,6] The most detected variant of BCR-ABL in CML is P210 BCR-ABL1 that occasionally presents in ALL and AML. Immunological targeted therapy against these markers resulted in depletion of CML-LSC and reduce LSC engraftment.[55] In a study of single-cell gene expression analysis combined with an immunophenotypic screening of CML-LSC, an aberrant expression of CML-LSC surface markers CD25, CD26, and interleukin[1] receptor accessory protein (IL1RAP) was detected These markers were found to be downregulated after TKI administration.[52] In contrast to normal stem cells, IL1RAP is a tight marker of BCR-ABL positive cells, and CD176 is a hematopoietic stem cell marker, co-expressed on CD34+/BCR-ABL+ cells of peripheral blood from CML patients. A high level of miR-451 at diagnosis was significantly correlated

11. Rowley JD

Findings

27. Apperley JF