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MYELODYSPLASTIC SYNDROME

Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia

Abstract

Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease.

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Fig. 1: Co-occurrence of TET2 mutations and KDM6B overexpression in human CMML.
Fig. 2: Tet2 deficient mice with KDM6B overexpression display enhanced CMML-like phenotypes.
Fig. 3: Tet2 deficiency and KDM6B overexpression affects BM HSPC numbers and function.
Fig. 4: Transcriptional alterations in of BM HSPCs in mice with concurrent Tet2 deficiency and KDM6B overexpression.
Fig. 5: Targeting KDM6B alters BM repopulating capability of double-lesion BM cells.
Fig. 6: Targeting KDM6B decreases human cell chimerism in PDX models of CMML.

References

  1. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.

    PubMed  Article  Google Scholar 

  2. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–42.

    CAS  PubMed  Article  Google Scholar 

  3. Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gaken J, Lea NC, et al. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood. 2010;116:3923–32.

    CAS  PubMed  Article  Google Scholar 

  4. Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lepine G, et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130:753–62.

    CAS  PubMed  Article  Google Scholar 

  5. Genovese G, Jaiswal S, Ebert BL, McCarroll SA. Clonal hematopoiesis and blood-cancer risk. N Engl J Med. 2015;372:1071–2.

    CAS  PubMed  Article  Google Scholar 

  6. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Jaiswal S, Ebert BL Clonal hematopoiesis in human aging and disease. Science. 2019;366:eaan4673.

  8. Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM, Mayassi T, et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 2018;557:580–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Cai ZG, Kotzin JJ, Ramdas B, Chen SS, Nelanuthala S, Palam LR, et al. Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis. Cell Stem Cell. 2018;23:833.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Muto T, Walker CS, Choi K, Hueneman K, Smith MA, Gul Z, et al. Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs. Nat Immunol. 2020;21:535–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev. 2009;8:18–30.

    CAS  PubMed  Article  Google Scholar 

  12. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:505–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Trowbridge JJ, Starczynowski DT Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS. J Exp Med. 2021;218:e20201544.

  15. Wei Y, Dimicoli S, Bueso-Ramos C, Chen R, Yang H, Neuberg D, et al. Toll-like receptor alterations in myelodysplastic syndrome. Leukemia. 2013;27:1832–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Fang J, Bolanos LC, Choi K, Liu X, Christie S, Akunuru S, et al. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol. 2017;18:236–45.

    CAS  PubMed  Article  Google Scholar 

  18. Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, et al. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 2013;24:90–104.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Dimicoli S, Wei Y, Bueso-Ramos C, Yang H, Dinardo C, Jia Y, et al. Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes. PLoS One. 2013;8:e71120.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N, et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med. 2015;212:1967–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16:49–58.

    CAS  PubMed  Article  Google Scholar 

  22. Smith MA, Choudhary GS, Pellagatti A, Choi K, Bolanos LC, Bhagat TD, et al. U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat Cell Biol. 2019;21:640–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449:731–4.

    CAS  PubMed  Article  Google Scholar 

  24. Wei Y, Zheng H, Bao N, Jiang S, Bueso-Ramos CE, Khoury J, et al. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice. Blood Adv. 2018;2:2491–504.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Wei Y, Chen R, Dimicoli S, Bueso-Ramos C, Neuberg D, Pierce S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia. 2013;27:2177–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 2009;28:3341–52.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Esplin BL, Shimazu T, Welner RS, Garrett KP, Nie L, Zhang Q, et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol. 2011;186:5367–75.

    CAS  PubMed  Article  Google Scholar 

  28. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20:11–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Montalban-Bravo G, Darbaniyan F, Kanagal-Shamanna R, Ganan-Gomez I, Class CA, Sasaki K, et al. Type I interferon upregulation and deregulation of genes involved in monopoiesis in chronic myelomonocytic leukemia. Leuk Res. 2021;101:106511.

    CAS  PubMed  Article  Google Scholar 

  30. Herold M, Schmalzl F, Zwierzina H. Increased serum interleukin 6 levels in patients with myelodysplastic syndromes. Leuk Res. 1992;16:585–8.

    CAS  PubMed  Article  Google Scholar 

  31. Yoh SM, Schneider M, Seifried J, Soonthornvacharin S, Akleh RE, Olivieri KC, et al. PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1. Cell. 2015;161:1293–305.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Croft D, O’Kelly G, Wu G, Haw R, Gillespie M, Matthews L, et al. Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res. 2011;39:D691–7. Database issue

    CAS  PubMed  Article  Google Scholar 

  33. Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015;15:362–74.

    CAS  PubMed  Article  Google Scholar 

  34. Yamashita M, Passegue E. TNF-alpha coordinates hematopoietic stem cell survival and myeloid regeneration. Cell Stem Cell. 2019;25:357–72 e7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Nilles N, Fahrenkrog B. Taking a Bad Turn: Compromised DNA Damage Response in Leukemia. Cells. 2017;6:11.

  36. Cuartero S, Weiss FD, Dharmalingam G, Guo Y, Ing-Simmons E, Masella S, et al. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat Immunol. 2018;19:932–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.

    CAS  PubMed  Article  Google Scholar 

  38. Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488:404–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Nakamura S, Ohnishi K, Yoshida H, Shinjo K, Takeshita A, Tohyama K, et al. Retrovirus-mediated gene transfer of granulocyte colony-stimulating factor receptor (G-CSFR) cDNA into MDS cells and induction of their differentiation by G-CSF. Cytokines Cell Mol Ther. 2000;6:61–70.

    CAS  PubMed  Article  Google Scholar 

  40. Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rgamma(null) humanized mice. Blood. 2011;117:3076–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Yoshimi A, Balasis ME, Vedder A, Feldman K, Ma Y, Zhang H, et al. Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML. Blood. 2017;130:397–407.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Zhang Y, He L, Selimoglu-Buet D, Jego C, Morabito M, Willekens C, et al. Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines. Blood Adv. 2017;1:972–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208:1189–201.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Mallaney C, Ostrander EL, Celik H, Kramer AC, Martens A, Kothari A, et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia. 2019;33:2506–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Lindsley RC, Ebert BL. The biology and clinical impact of genetic lesions in myeloid malignancies. Blood. 2013;122:3741–8.

    CAS  PubMed  Article  Google Scholar 

  46. Nguyen HD, Leong WY, Li W, Reddy PNG, Sullivan JD, Walter MJ. et al. Spliceosome mutations induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes. Cancer Res. 2018;78:5363–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med. 2014;20:1394–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature. 2014;514:513–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We also acknowledge Cancer Prevention & Research Institute of Texas award RP101320 that supported our initial study about KDM6B in MDS and CMML.

Funding

This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672, the generous philanthropic donations to the University of Texas MD Anderson MDS/AML Moon Shot, the Leukemia Research Foundation, and the Leukemia SPORE Development Award.

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YW: Concept and design; collection and assembly of data; data analysis and interpretation; manuscript writing; and final approval of manuscript. RK-S, HZ, NB, PPL, CC, FD, YL, KL, HY, GM-B, IG-G, K-AD, SC: Collection and assembly of data; data analysis and interpretation; manuscript writing; and final approval of manuscript. KAS: Administrative support; data analysis and interpretation; manuscript writing; and final approval of manuscript. GG-M: Conception and design; administrative support; provision of study materials or patients; collection and assembly of data; manuscript writing; and final approval of manuscript.

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Correspondence to Yue Wei or Guillermo Garcia-Manero.

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Wei, Y., Kanagal-Shamanna, R., Zheng, H. et al. Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia. Leukemia (2022). https://doi.org/10.1038/s41375-022-01605-1

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