Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Abstract

Chronic myelogenous leukemia (CML) stem cells (LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here, we show that although miR-126 supports the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels are lower in CML LSCs as compared to normal long-term hematopoietic stem cells (LT-HSCs). Down-regulation of miR-126 levels in CML LSCs is due to phosphorylation of SPRED1 by BCR-ABL, leading to inhibition of the RAN/EXP-5/RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using CML mouse models with conditional miR-126 knock-out (KO) in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment causes an undesired increase in endogenous miR-126 levels, thereby enhancing LSC quiescence and persistence. miR-126 KO in LSCs and/or ECs, or treatment with a CpG-miR-126 inhibitor targeting miR-126 in both LSCs and ECs, enhances the in vivo anti-leukemic effects of TKI treatment and strongly diminishes LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in CML.

miRNome profiling of clonal stem cells in Ph+CML

“…Interestingly, miR-126-3p levels in our NGS-cohort were lower than those of mi-126-5p, and therefore it was not selected for further validation. However, they were lower in LSC compared to CML HSC and HD HSC (0.59 and 0.35-fold-change, respectively), in agreement with the data reported by Zhang et al 30 . Additionally, the authors showed that miR-126-3p can be transferred from BMderived endothelial cells to primitive hematopoietic cells by extracellular vesicles.…”

“…However, there are no reports of miR-126-5p in this system 30 . Interestingly, miR-126-3p levels in our NGS-cohort were lower than those of mi-126-5p, and therefore it was not selected for further validation.…”

“…In CML, global microRNA depletion in patient samples has not been reported so far. In the work of Zhang et al, they showed, in K562 cells and CML CD34 + cells, that BCR-ABL1 can affect the export of miR-126 precursors from the nucleus to the cytoplasm, through phosphorylation of SPRED1, a negative regulator of RAS superfamily proteins, interfering with Ran-exportin 5-RCC1 complex 30 . Interestingly, this effect was reversible by treatment with Nilotinib.…”

The 14q32.31DLK1-DIO3 MIR300 tumor suppressorpromotes leukemogenesis by inducing cancer stem cell quiescence and inhibiting NK cell anti-cancer immunity

“…mir-16 family) have been associated with CSC expansion and maintenance 4 . For example, miR-126, which targets CDK3, inhibits qLSC re-entry into cycle but does not induce quiescence and, importantly, it is not acting as a tumor suppressor in AML/CML LSCs 9,10 . Less clear and controversial is the role of miR-221/222/223 in CSC quiescence since their expression is regulated by MSCs in a tumor-and cell type-specific manner but also increases in response to mitogenic stimuli to induce CDK4/CCND1-dependent cell cycle re-entry 4,11 .…”

“…Several miRNAs have been associated with CSC expansion and maintenance 4 and PP2A inactivation 8 ; however, a clear causal link between expression of specific miRNAs, persistence of the drug-resistant quiescent CSCs and PP2A loss-of-function is still missing. Furthermore, these miRNAs mostly act as regulators of CSC survival, maintenance into dormancy and cell cycle re-entry but it is unclear whether any of them directly promotes CSC cell cycle exit 4,[9][10][11] .…”