Salt-inducible kinase inhibition sensitizes human acute myeloid leukemia cells to all-trans retinoic acid-induced differ
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ORIGINAL ARTICLE
Salt‑inducible kinase inhibition sensitizes human acute myeloid leukemia cells to all‑trans retinoic acid‑induced differentiation Xue‑Wen Zhang1,2 · Xing Shen2 · Wen‑Yue Long2 · He Xiao3 · Feng‑Jun Li2 · Shuang Xing2 · Guo‑Lin Xiong2 · Zu‑Yin Yu1,2 · Yu‑Wen Cong1,2 Received: 7 July 2020 / Revised: 20 September 2020 / Accepted: 5 October 2020 © Japanese Society of Hematology 2020
Abstract Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy. Keywords Salt-inducible kinase · ATRA · Differentiation · Acute myeloid leukemia · Akt
Introduction Acute myeloid leukemia (AML), the most common adult leukemia, is characterized by defective differentiation, aberrant proliferation, and inappropriate survival of clonal precursor myeloid cells [1]. Although remission can be achieved in most de novo AML patients, the leukemia will Xue-Wen Zhang and Xing Shen have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-03026-1) contains supplementary material, which is available to authorized users. * Zu‑Yin Yu [email protected] * Yu‑Wen Cong [email protected] 1
Guangdong Pharmaceutical University, Guangzhou, China
2
Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
3
Department of Molecular Immunology, Institute of Pharmacology and Toxicology, Beijing, China
recur with poor outcomes. The only exception is treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) differentiation therapy. In APL, treatment with ATRA alone or in combination with anthracycline-based chemotherapy, results in myeloid differentiation of the leukemic blasts and leads to a high rate of complete remission and the long-term survival [2]. However, ATRA is not clinically useful for the non-APL AML subtypes. Therefore, there is an urgent need to develop new differentiation therapies to improve the efficiency of ATRA against a wide range of other myeloid malignancies
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