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Review
. 2021 Dec 15:10:1288.
doi: 10.12688/f1000research.74570.2. eCollection 2021.

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

Mohammad Al Hamad  1
Affiliations
Review

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

Mohammad Al Hamad. F1000Res. .

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.

Keywords: BCR-ABL; Chronic myeloid leukemia; Kinase domain mutations; Leukemic stem cell; Tyrosine kinase inhibitors; mi RNA..

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Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Schematic illustrates various mechanisms of CML-LSC (chronic myeloid leukemia-leukemic stem cell) resistance and response to TKI (tyrosine kinase inhibitor).
See this image and copyright information in PMC

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