MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors

Wang, Lisheng; Li, Ling; Li, Liang; Chu, Su; Shiang, Keh-Dong; Li, Min; Sun, Huiyan; Xu, Jun; Xiao, Fengjun; Sun, Guihua; Rossi, John J.; Ho, YinWei; Bhatia, Smita

doi:10.1182/blood-2014-06-581926

Cited by 125 publications

(112 citation statements)

References 49 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…We show here that miR-486-5p is not merely a marker of erythroid progenitors, but rather a regulator of the erythroid phenotype of ML-DS leukemic cells. Our results are supported by independent observations of Bhatia et al , 56 in which ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34 1 cells. Interestingly, miR-486-5p activates AKT ( Figure 5A,B), which has been previously shown to be important for erythroid differentiation.…”

Section: Discussionsupporting

confidence: 82%

See 1 more Smart Citation

MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome

Shaham

Vendramini

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 82%

“…We speculate that miR-486-5p provides this "missing link," as it is a strong activator of AKT in ML-DS. The similar observations in chronic ML by Bhatia et al 56 suggest that miR-486-5p may be an important oncogene in several hematopoietic myeloid malignancies characterized by dependency on the PI3K/AKT pathway. For personal use only.…”

Section: Discussionsupporting

confidence: 67%

MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome

Shaham

Vendramini

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

“…Interestingly, miR-486 is reported to be involved in normal erythropoiesis and modulates drug resistance in CML. 48 Most notably, miR-486-5p was reported to modulate response to imatinib in CML progenitor cells. 48 The mechanism by which these variants affect response awaits further clinical and experimental evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…48 Most notably, miR-486-5p was reported to modulate response to imatinib in CML progenitor cells. 48 The mechanism by which these variants affect response awaits further clinical and experimental evaluation. Alternatively, it is plausible that other variants in linkage disequilibrium with the ASXL1 and BIM variants that were not detected using our targeted sequencing approach are responsible for the associations detected by this study.…”

Section: Discussionmentioning

confidence: 99%

ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure

et al. 2017

View full text Add to dashboard Cite

Key Points• Germ line variants in ASXL1 and BIM are strong biomarkers of response to imatinib in chronic phase CML.• A combined Sokal risk and ASXL1 and BIM variant model identified a subgroup of patients with the greatest risk of treatment failure.Scoring systems used at diagnosis of chronic myeloid leukemia (CML), such as Sokal risk, provide important response prediction for patients treated with imatinib. However, the sensitivity and specificity of scoring systems could be enhanced for improved identification of patients with the highest risk. We aimed to identify genomic predictive biomarkers of imatinib response at diagnosis to aid selection of first-line therapy. P 5 .041), progression to AP/BC (12% vs 1%; P 5 .034), FFS (P , .001), and MRs (P , .001).The ultra-high-risk patients may be candidates for more potent or combination first-line therapy. These data suggest that germ line genetic variation contributes to the heterogeneity of response to imatinib and may contribute to a prognostic risk score that allows early optimization of therapy.

show abstract

“…30 Further evaluation of this mechanism is warranted in future studies. The studies ofÅngerstam et al, and our own analyses, show that IL-1 receptor expression on CML LSC is not reduced by BCR-ABL kinase inhibition.Ångerstam et al further show that TKI-treated CML stem cells maintain signaling responses to IL-1 stimulation.…”

Section: Il-1ra and Nil Inhibit Inflammatory Signaling In CML Lscmentioning

confidence: 99%

Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor–treated CML stem cells

Zhang

Chu

Agarwal

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• CML LSC demonstrate increased IL-1 receptor expression and enhanced signaling response.• Inhibition of IL-1 signaling using the antagonist IL-1RA enhances targeting of CML LSC in combination with TKI.Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow. We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1 receptor accessory protein and IL-1 receptor type 1 (IL-1R1), and enhanced sensitivity to IL-1-induced NF-kB signaling compared with normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment and that IL-1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML. (Blood. 2016;128(23):2671-2682

show abstract

MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors

Abstract: Key Points miR-486-5p is expressed in megakaryocyte-erythroid progenitors and regulates growth and survival by regulating FOXO1 and AKT. miR-486-5p is overexpressed in CML progenitors and enhances their growth, survival, and response to tyrosine kinase inhibitors.

Cited by 125 publications

References 49 publications

MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome

MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome

ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure

Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor–treated CML stem cells

Contact Info

Product

Resources

About