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The miR-106b-25 cluster mediates drug resistance in myeloid leukaemias by inactivating multiple apoptotic genes

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Abstract

Drug resistance is a major obstacle to the successful treatment of cancer. The role of the miR-106b-25 cluster in drug resistance of haematologic malignancies has not yet been elucidated. Here, we show that the miR-106b-25 cluster mediates resistance to therapeutic agents with structural and mechanistic dissimilarity in vitro and in vivo. RNA sequencing data revealed that overexpression of the miR-106b-25 cluster or its individual miRNAs resulted in downregulation of multiple key regulators of apoptotic pathways. Luciferase reporter assay identified TP73 as a direct target of miR-93 and miR-106b, BAK1 as a direct target of miR-25 and CASP7 as a direct target of all three miRNAs. We also showed that inhibitors of the miR-106b-25 cluster and BCL-2 exert synergistic effects on apoptosis induction in primary myeloid leukaemic cells. Thus, the members of the miR-106b-25 cluster may jointly contribute to myeloid leukaemia drug resistance by inactivating multiple apoptotic genes. Targeting this cluster could be a promising combination strategy in patients resistant to therapeutic agents that induce apoptosis.

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All data supporting the findings of this study are available within the article and its supplementary information file or are available from the corresponding author upon request.

References

  1. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29:487–94.

    Article  Google Scholar 

  2. Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol. 2018;93:1267–91.

    Article  Google Scholar 

  3. Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016. https://doi.org/10.1126/scitranslmed.aag1180.

    Article  Google Scholar 

  4. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640–53.

    Article  CAS  Google Scholar 

  5. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.

    Article  CAS  Google Scholar 

  6. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase ii study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    Article  CAS  Google Scholar 

  7. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  Google Scholar 

  8. Parry N, Wheadon H, Copland M. The application of BH3 mimetics in myeloid leukemias. Cell Death Dis. 2021;12:222.

    Article  CAS  Google Scholar 

  9. Sarkozy C, Gardin C, Gachard N, Merabet F, Turlure P, Malfuson JV, et al. Outcome of older patients with acute myeloid leukemia in first relapse. Am J Hematol. 2013;88:758–64.

    Article  CAS  Google Scholar 

  10. Klumper E, Pieters R, Veerman AJ, Huismans DR, Loonen AH, Hahlen K, et al. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood. 1995;86:3861–8.

    Article  CAS  Google Scholar 

  11. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.

    Article  CAS  Google Scholar 

  12. Gebru MT, Wang HG. Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia. J Hematol Oncol. 2020;13:155.

    Article  Google Scholar 

  13. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  Google Scholar 

  14. Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 2005;122:553–63.

    Article  CAS  Google Scholar 

  15. Fabbri M, Garzon R, Andreeff M, Kantarjian HM, Garcia-Manero G, Calin GA. MicroRNAs and noncoding RNAs in hematological malignancies: molecular, clinical and therapeutic implications. Leukemia. 2008;22:1095–105.

    Article  CAS  Google Scholar 

  16. Liu Y, Cheng Z, Pang Y, Cui L, Qian T, Quan L, et al. Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia. J Hematol Oncol. 2019;12:51.

    Article  Google Scholar 

  17. Mehlich D, Garbicz F, Wlodarski PK. The emerging roles of the polycistronic miR-106b approximately 25 cluster in cancer - a comprehensive review. Biomed Pharmacother. 2018;107:1183–95.

    Article  CAS  Google Scholar 

  18. Zhou Y, Hu Y, Yang M, Jat P, Li K, Lombardo Y, et al. The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300. Cell Death Differ. 2013;21:462–74.

    Article  Google Scholar 

  19. Li SG, Shi QW, Yuan LY, Qin LP, Wang Y, Miao YQ, et al. C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2018;37:51.

    Article  Google Scholar 

  20. Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 2008;68:6162–70.

    Article  CAS  Google Scholar 

  21. Andersson LC, Nilsson K, Gahmberg CG. K562–a human erythroleukemic cell line. Int J Cancer. 1979;23:143–7.

    Article  CAS  Google Scholar 

  22. Fleck RA, Romero-Steiner S, Nahm MH. Use of HL-60 cell line to measure opsonic capacity of pneumococcal antibodies. Clin Diagn Lab Immunol. 2005;12:19–27.

    CAS  Google Scholar 

  23. Auwerx J. The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia. 1991;47:22–31.

    Article  CAS  Google Scholar 

  24. Sakurada K, Zheng B, Kuo JF. Comparative effects of protein phosphatase inhibitors (okadaic acid and calyculin A) on human leukemia HL60, HL60/ADR and K562 cells. Biochem Biophys Res Commun. 1992;187:488–92.

    Article  CAS  Google Scholar 

  25. Yang CZ, Luan FJ, Xiong DS, Liu BR, Xu YF, Gu KS. Multidrug resistance in leukemic cell line K562/A02 induced by doxorubicin. Zhongguo Yao Li Xue Bao. 1995;16:333–7.

    Google Scholar 

  26. Si X, Zhang X, Hao X, Li Y, Chen Z, Ding Y, et al. Upregulation of miR-99a is associated with poor prognosis of acute myeloid leukemia and promotes myeloid leukemia cell expansion. Oncotarget. 2016;7:78095–109.

    Article  Google Scholar 

  27. Lee JY, Kim S, Hwang DW, Jeong JM, Chung JK, Lee MC, et al. Development of a dual-luciferase reporter system for in vivo visualization of MicroRNA biogenesis and posttranscriptional regulation. J Nucl Med. 2008;49:285–94.

    Article  CAS  Google Scholar 

  28. Rastgoo N, Wu J, Liu A, Pourabdollah M, Atenafu EG, Reece D, et al. Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma. Haematologica. 2020;105:2813–23.

    Article  CAS  Google Scholar 

  29. Soneson C, Delorenzi M. A comparison of methods for differential expression analysis of RNA-seq data. BMC Bioinformatics. 2013;14:91.

    Article  Google Scholar 

  30. da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

    Article  CAS  Google Scholar 

  31. Kukurba KR, Montgomery SB. RNA Sequencing and Analysis. Cold Harb Protoc. 2015;2015:951–69.

    Google Scholar 

  32. Ji F, Sadreyev RI. RNA-seq: basic bioinformatics analysis. Curr Protoc Mol Biol. 2018;124:e68.

    Article  Google Scholar 

  33. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003;22:9030–40.

    Article  CAS  Google Scholar 

  34. Conforti F, Sayan AE, Sreekumar R, Sayan BS. Regulation of p73 activity by post-translational modifications. Cell Death Dis. 2012;3:e285.

    Article  CAS  Google Scholar 

  35. Green DR. Apoptotic pathways: the roads to ruin. Cell. 1998;94:695–8.

    Article  CAS  Google Scholar 

  36. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87.

    Article  CAS  Google Scholar 

  37. Swift LP, Rephaeli A, Nudelman A, Phillips DR, Cutts SM. Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 2006;66:4863–71.

    Article  CAS  Google Scholar 

  38. Gamas P, Marchetti S, Puissant A, Grosso S, Jacquel A, Colosetti P, et al. Inhibition of imatinib-mediated apoptosis by the caspase-cleaved form of the tyrosine kinase Lyn in chronic myelogenous leukemia cells. Leukemia. 2009;23:1500–6.

    Article  CAS  Google Scholar 

  39. Rebecca Valentin SG. Matthew S Davids the rise of apoptosis targeting apoptosis in hematologic malignancies. Blood. 2018;132:1248–64.

    Article  Google Scholar 

  40. Kan T, Sato F, Ito T, Matsumura N, David S, Cheng Y, et al. The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology. 2009;136:1689–700.

    Article  CAS  Google Scholar 

  41. Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res. 2008;68:8191–4.

    Article  CAS  Google Scholar 

  42. Hudson RS, Yi M, Esposito D, Glynn SA, Starks AM, Yang Y, et al. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene. 2013;32:4139–47.

    Article  CAS  Google Scholar 

  43. Niu J, Xue A, Chi Y, Xue J, Wang W, Zhao Z, et al. Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene. 2016;35:1302–13.

    Article  CAS  Google Scholar 

  44. Nie ZY, Yao M, Yang Z, Yang L, Liu XJ, Yu J, et al. De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance. J Exp Clin Cancer Res. 2020;39:17.

    Article  CAS  Google Scholar 

  45. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375–88.

    Article  CAS  Google Scholar 

  46. Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4:362–75.

    Article  CAS  Google Scholar 

  47. Ko TK, Chuah CT, Huang JW, Ng KP, Ong ST. The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget. 2014;5:9033–8.

    Article  Google Scholar 

  48. Massimino M, Vigneri P, Stella S, Tirro E, Pennisi MS, Parrinello LN, et al. Combined inhibition of Bcl2 and Bcr-Abl1 exercises anti-leukemia activity but does not eradicate the primitive leukemic cells. J Clin Med. 2021;10:5606.

    Article  CAS  Google Scholar 

  49. Wilson TR, Johnston PG, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets. 2009;9:307–19.

    Article  CAS  Google Scholar 

  50. Anusha Dalal H, Subramanian SVPS, Gowda DAHK, et al. Exovesicular-Shh confers Imatinib resistance by upregulating Bcl2 expression in chronic myeloid leukemia with variant chromosomes. Cell Death Dis. 2021. https://doi.org/10.1038/s41419-021-03542-w.

    Article  Google Scholar 

  51. Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell. 2003;3:387–402.

    Article  CAS  Google Scholar 

  52. Feeley KP, Adams CM, Mitra R, Eischen CM. Mdm2 Is required for survival and growth of p53-deficient cancer cells. Cancer Res. 2017;77:3823–33.

    Article  CAS  Google Scholar 

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Funding

This work was supported in part by National Natural Science Foundation of China (grant numbers 81970120, 81770128, 81890990, 81800139), National Key Research and Development Program of China (grant number 2020YFE0203000) and Chinese Academy of Medical Sciences (grant number 2019–1002-38).

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China

    Mingying Zhang, Fangnan Xiao, Yunan Li, Zizhen Chen, Xiaoyun Zhang, Xiaoru Zhang, Junzhe Song & Yuan Zhou

  2. Department of Hematology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, 300211, China

    Yuhui Zhang & Jie Bai

  3. School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, China

    Xiaohui Si

  4. Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W12 0NN, UK

    Ernesto Yagüe

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  1. Mingying Zhang
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  3. Yunan Li
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  11. Ernesto Yagüe
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Contributions

YZ and MYZ designed the study. MYZ, FNX, YNL, ZZC, XYZ, XRZ and JZS performed the experiments. ZZC performed RNA-Seq analysis. MYZ, XHS, EY and YZ discussed and analysed the data. MYZ, YHZ and JB collected patients’ information. MYZ, ZZC, EY and YZ wrote the manuscript. All authors reviewed, edited and approved the manuscript.

Corresponding authors

Correspondence to Ernesto Yagüe or Yuan Zhou.

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All the authors declare that they have no conflict of interest.

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All animal experiments complied with the ARRIVE guidelines and were approved by the Animal Research Committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College.

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Zhang, M., Xiao, F., Li, Y. et al. The miR-106b-25 cluster mediates drug resistance in myeloid leukaemias by inactivating multiple apoptotic genes. Int J Hematol 117, 236–250 (2023). https://doi.org/10.1007/s12185-022-03483-w

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