Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a

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Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a. / Wilkes, Mark C.; Siva, Kavitha; Varetti, Gianluca; Mercado, Jacqueline; Wentworth, Ethan P.; Perez, Cristina A.; Saxena, Mallika; Kam, Sharon; Kapur, Simryn; Chen, Jun; Narla, Anu; Glader, Bert; Lin, Shou; Serrano, Manuel; Flygare, Johan; Sakamoto, Kathleen M.

In: Experimental Hematology, Vol. 91, 01.11.2020, p. 65-77.

Research output: Contribution to journalArticle

Harvard

Wilkes, MC, Siva, K, Varetti, G, Mercado, J, Wentworth, EP, Perez, CA, Saxena, M, Kam, S, Kapur, S, Chen, J, Narla, A, Glader, B, Lin, S, Serrano, M, Flygare, J & Sakamoto, KM 2020, 'Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a', Experimental Hematology, vol. 91, pp. 65-77. https://doi.org/10.1016/j.exphem.2020.09.187

APA

Wilkes, M. C., Siva, K., Varetti, G., Mercado, J., Wentworth, E. P., Perez, C. A., Saxena, M., Kam, S., Kapur, S., Chen, J., Narla, A., Glader, B., Lin, S., Serrano, M., Flygare, J., & Sakamoto, K. M. (2020). Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a. Experimental Hematology, 91, 65-77. https://doi.org/10.1016/j.exphem.2020.09.187

CBE

Wilkes MC, Siva K, Varetti G, Mercado J, Wentworth EP, Perez CA, Saxena M, Kam S, Kapur S, Chen J, Narla A, Glader B, Lin S, Serrano M, Flygare J, Sakamoto KM. 2020. Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a. Experimental Hematology. 91:65-77. https://doi.org/10.1016/j.exphem.2020.09.187

MLA

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Author

Wilkes, Mark C. ; Siva, Kavitha ; Varetti, Gianluca ; Mercado, Jacqueline ; Wentworth, Ethan P. ; Perez, Cristina A. ; Saxena, Mallika ; Kam, Sharon ; Kapur, Simryn ; Chen, Jun ; Narla, Anu ; Glader, Bert ; Lin, Shou ; Serrano, Manuel ; Flygare, Johan ; Sakamoto, Kathleen M. / Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a. In: Experimental Hematology. 2020 ; Vol. 91. pp. 65-77.

RIS

TY - JOUR

T1 - Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a

AU - Wilkes, Mark C.

AU - Siva, Kavitha

AU - Varetti, Gianluca

AU - Mercado, Jacqueline

AU - Wentworth, Ethan P.

AU - Perez, Cristina A.

AU - Saxena, Mallika

AU - Kam, Sharon

AU - Kapur, Simryn

AU - Chen, Jun

AU - Narla, Anu

AU - Glader, Bert

AU - Lin, Shou

AU - Serrano, Manuel

AU - Flygare, Johan

AU - Sakamoto, Kathleen M.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3′ untranslated region (3′UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.

AB - Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3′ untranslated region (3′UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.

U2 - 10.1016/j.exphem.2020.09.187

DO - 10.1016/j.exphem.2020.09.187

M3 - Article

C2 - 32926965

AN - SCOPUS:85091607173

VL - 91

SP - 65

EP - 77

JO - Experimental Hematology

JF - Experimental Hematology

SN - 1873-2399

ER -