MiR-125a-3p and MiR-320b Differentially Expressed in Patients with Chronic Myeloid Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Imatinib Mesylate

Martins, Juliana Ravelli Baldassarre; Moraes, Leonardo Nazário de; Cury, Sarah Santiloni; Capannacci, Juliana; Carvalho, Robson Francisco; Nogueira, Célia Regina; Hokama, Newton Key; Hokama, Paula de Oliveira Montandon

doi:10.3390/ijms221910216

Cited by 5 publications

(1 citation statement)

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“…Since miRNAs have been shown to specifically contribute to CML patients' sensitivity to TKI by affecting the survival of primitive stem cells [10], and LVSELs and LHSCs were found to show a difference in their survival in the presence of IM in this study, we asked whether miRNA expression could be deregulated in these two subpopulations. Among the miRNAs known as key regulators that exert their effects on CML LSC maintenance and/or resistance to TKI through diverse mechanisms, we selected miR-21 [14], miR-29b, miR-30e [17], miR-126 [18], miR-130a [19], miR-378 [20], miR-146a [21], miR-199a [22], miR-320b [23], miR-451 [24], miR-486 [25], and miR-494 to evaluate their expression levels in the subpopulations of expanded stem cells isolated from biopsies of newly diagnosed patients that were exposed or not exposed to IM. We first sorted defined subsets of LHSCs (Lin − CD34 + CD45 + ) and LVSELs (Lin − CD34 + CD45 − ) from untreated and treated CD34 + SCs isolated from patients affected by CML and not receiving TKI.…”

Section: Mirna Expression In Linmentioning

confidence: 99%

Stem Cell Responsiveness to Imatinib in Chronic Myeloid Leukemia

Lahlil,

Aries,

Scrofani

et al. 2023

IJMS

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the presence of the BCR-ABL fusion gene, which results from the Philadelphia chromosome. Since the introduction of tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM), the clinical outcomes for patients with CML have improved significantly. However, IM resistance remains the major clinical challenge for many patients, underlining the need to develop new drugs for the treatment of CML. The basis of CML cell resistance to this drug is unclear, but the appearance of additional genetic alterations in leukemic stem cells (LSCs) is the most common cause of patient relapse. However, several groups have identified a rare subpopulation of CD34+ stem cells in adult patients that is present mainly in the bone marrow and is more immature and pluripotent; these cells are also known as very small embryonic-like stem cells (VSELs). The uncontrolled proliferation and a compromised differentiation possibly initiate their transformation to leukemic VSELs (LVSELs). Their nature and possible involvement in carcinogenesis suggest that they cannot be completely eradicated with IM treatment. In this study, we demonstrated that cells from CML patients with the VSELs phenotype (LVSELs) similarly harbor the fusion protein BCR-ABL and are less sensitive to apoptosis than leukemic HSCs after IM treatment. Thus, IM induces apoptosis and reduces the proliferation and mRNA expression of Ki67 more efficiently in LHSCs than in leukemic LVSELs. Finally, we found that the expression levels of some miRNAs are affected in LVSELs. In addition to the tumor suppressor miR-451, both miR-126 and miR-21, known to be responsible for LSC leukemia-initiating capacity, quiescence, and growth, appear to be involved in IM insensitivity of LVSELs CML cell population. Targeting IM-resistant CML leukemic stem cells by acting via the miRNA pathways may represent a promising therapeutic option.

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