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miR-29c&b2 encourage extramedullary infiltration resulting in the poor prognosis of acute myeloid leukemia

Abstract

Extramedullary infiltration (EMI), as a concomitant symptom of acute myeloid leukemia (AML), is associated with low complete remission and poor prognosis in AML. However, the mechanism of EMI remains indistinct. Clinical trials showed that increased miR-29s were associated with a poor overall survival in AML [14]. Nevertheless, they were proved to work as tumor suppressor genes by encouraging apoptosis and inhibiting proliferation in vitro. These contradictory results led us to the hypothesis that miR-29s may play a notable role in the prognosis of AML rather than leukemogenesis. Thus, we explored the specimens of AML patients and addressed this issue into miR-29c&b2 knockout mice. As a result, a poor overall survival and invasive blast cells were observed in high miR-29c&b2-expression patients, and the wildtype mice presented a shorter survival with heavier leukemia infiltration in extramedullary organs. Subsequently, we found that the miR-29c&b2 inside leukemia cells promoted EMI, but not the one in the microenvironment. The analysis of signal pathway revealed that miR-29c&b2 could target HMG-box transcription factor 1 (Hbp1) directly, then reduced Hbp1 bound to the promoter of non-muscle myosin IIB (Myh10) as a transcript inhibitor. Thus, increased Myh10 encouraged the migration of leukemia cells. Accordingly, AML patients with EMI were confirmed to have high miR-29c&b2 and MYH10 with low HBP1. Therefore, we identify that miR-29c&b2 contribute to the poor prognosis of AML patients by promoting EMI, and related genes analyses are prospectively feasible in assessment of AML outcome.

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Fig. 1: miR-29c&miR-29b2 were related to poor outcome and severe EMI in AML.
Fig. 2: miR-29c&b2 in leukemia cells encouraged the EMI.
Fig. 3: miR-29c/miR-29b2-3p contributes to the migration of AML cells by suppressing Hbp1.
Fig. 4: Hbp1 mediates the transcription of Myh10.
Fig. 5: AML patients with liver or splenomegaly expressed high miR-29c&b2 and MYH10 with low HBP1.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81870132, 81261120568) and the Science and Technology Commission of Shanghai Municipality (18DZ2290700,18DZ2293500).

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Correspondence to Jian Fei or Jun Shi.

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Ethics approval and consent to participate

All human bone marrow specimens were collected from patients diagnosed with AML at the Shanghai Ninth People’s Hospital, China, from 2016 to 2020. Informed consent was obtained from all patients and the project was approved by the Ethics Committee of Shanghai Ninth People’s Hospital. Six- to eight-week-old C57BL/6 or miR-29c&b2 knockout C57BL/6 mice were purchased from the Shanghai Model Organisms Center, Inc (Shanghai, China). Six- to eight-week-old NOD-SCID mice were purchased from Shanghai SLAC Laboratory Animal Co., Ltd (Shanghai, China). All experiments with mice were performed strictly in accordance with a protocol approved by the Administrative Panel on Laboratory Animal Care of the Shanghai Ninth People’s Hospital.

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Wei, Y., Lu, W., Yu, Y. et al. miR-29c&b2 encourage extramedullary infiltration resulting in the poor prognosis of acute myeloid leukemia. Oncogene 40, 3434–3448 (2021). https://doi.org/10.1038/s41388-021-01775-9

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