Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient

Cancer Gene Therapy volume 31, pages 484–494 (2024)Cite this article

Subjects

Abstract

Primary myelofibrosis (PMF) patients frequently have JAK2 (V617F), CALR (exon 9), or MPL (W515 or exon 10) strong driver gene mutation, which triggers abnormal activation of the JAK2-STATs signaling pathway that plays a complex role in the occurrence of PMF. However, about 10–15% of PMF patients have no above typical mutations in these strong driver genes, known as being “triple-negative”, which are associated with poor prognosis. In this paper, we reported a unique secondary acute myeloid leukemia (sAML) case transformed from triple-negative PMF combined with lung cancer and erythroderma occurrence at the same time, which has not been reported so far. Through whole blood exome sequencing, four novel noncanonical mutations were detected in key regulatory genes SH2B3 (Q748 and S710) and STAT5a (C350 and K354). Meanwhile, STAT5a-S710 and SH2B3-K354 noncanonical mutations gained strong malignant biofunction on promoting cell growth and tumorigenesis by accelerating the G1/S transition. In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A new case of complex multiple malignant tumors patient was found in southern China.
Fig. 2: SH2B3 and STAT5a novel mutations were identified by whole exome sequencing.
Fig. 3: STAT5a-S710 and SH2B3-C305/C354 mutations promoted the proliferation of AML cells.
Fig. 4: STAT5a-S710 and SH2B3-C305/C354 mutations facilitated the cell cycle from G1 to S phase transition in AML cells.
Fig. 5: SH2B3 and STAT5a novel mutations promoted the tumorigenesis of AML cells.
Fig. 6: STAT5a and SH2B3 novel mutations might promote tumor initiation and development via, respectively, activating p-STAT5a/c-Myc/ CyclinD1 and p-STAT3/p-AKT/p-ERK1/2.
Fig. 7: Ruxoitinib is an effective targeted drug for patients with STAT5a and SH2B3 novel mutations.
Fig. 8

Similar content being viewed by others

Data availability

Correspondence and requests for materials should be addressed to Hao Jiang (jianghao1209@csu.edu.cn).

References

  1. Tefferi A, Mudireddy M, Mannelli F, Begna KH, Patnaik MM, Hanson CA, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018;32:1200–10.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yogarajah M, Tefferi A. Leukemic transformation in myeloproliferative neoplasms: a literature review on risk, characteristics, and outcome. Mayo Clin Proc. 2017;92:1118–28.

    Article  CAS  PubMed  Google Scholar 

  3. Luque PD, Kralovics R, Skoda RC. Genetic basis and molecular profiling in myeloproliferative neoplasms. Blood. 2023;141:1909–21.

    Article  Google Scholar 

  4. Gangat N, Tefferi A. Myelofibrosis biology and contemporary management. Br J Haematol. 2020;191:152–70.

    Article  CAS  PubMed  Google Scholar 

  5. Morsia E, Gangat N. Myeloproliferative neoplasms with monocytosis. Curr Hematol Malig Rep. 2022;17:46–51.

    Article  PubMed  Google Scholar 

  6. Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021;96:145–62.

    Article  CAS  PubMed  Google Scholar 

  7. Thiele J, Kvasnicka HM, Orazi A, Gianelli U, Gangat N, Vannucchi AM, et al. The international consensus classification of myeloid neoplasms and acute Leukemias: myeloproliferative neoplasms. Am J Hematol. 2023;98:166–79.

    Article  CAS  PubMed  Google Scholar 

  8. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Klampfl T, Harutyunyan A, Berg T, Gisslinger B, Schalling M, Bagienski K, et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood. 2011;118:167–76.

    Article  CAS  PubMed  Google Scholar 

  10. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28:1472–7.

    Article  CAS  PubMed  Google Scholar 

  11. Tefferi A, Vannucchi AM. Genetic Risk assessment in myeloproliferative neoplasms. Mayo Clin Proc. 2017;92:1283–90.

    Article  CAS  PubMed  Google Scholar 

  12. Tefferi A, Nicolosi M, Mudireddy M, Szuber N, Finke CM, Lasho TL, et al. Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients. Am J Hematol. 2018;93:348–55.

    Article  CAS  PubMed  Google Scholar 

  13. Mascarenhas J, Gleitz H, Chifotides HT, Harrison CN, Verstovsek S, Vannucchi AM, et al. Biological drivers of clinical phenotype in myelofibrosis. Leukemia. 2023;37:255–64.

    Article  CAS  PubMed  Google Scholar 

  14. Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:801–21.

    Article  CAS  PubMed  Google Scholar 

  15. Loscocco GG, Vannucchi AM. Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives. Int J Hematol. 2022;115:626–44.

    Article  CAS  PubMed  Google Scholar 

  16. Mascarenhas J, Marcellino BK, Lu M, Kremyanskaya M, Fabris F, Sandy L, et al. A phase I study of panobinostat and ruxolitinib in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF). Leuk Res. 2020;88:106272.

    Article  CAS  PubMed  Google Scholar 

  17. Coltro G, Loscocco GG, Vannucchi AM. Classical Philadelphia-negative myeloproliferative neoplasms (MPNs): a continuum of different disease entities. Int Rev Cell Mol Biol. 2021;365:1–69.

    Article  CAS  PubMed  Google Scholar 

  18. Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35:1–17.

    Article  CAS  PubMed  Google Scholar 

  19. Zingariello M, Martelli F, Verachi P, Bardelli C, Gobbo F, Mazzarini M, et al. Novel targets to cure primary myelofibrosis from studies on Gata1(low) mice. IUBMB Life. 2020;72:131–41.

    Article  CAS  PubMed  Google Scholar 

  20. Lv K, Jiang J, Donaghy R, Riling CR, Cheng Y, Chandra V, et al. CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies. Genes Dev. 2017;31:1007–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang LN, Zhang ZT, Wang L, Wei HX, Zhang T, Zhang LM, et al. TGF-beta1/SH2B3 axis regulates anoikis resistance and EMT of lung cancer cells by modulating JAK2/STAT3 and SHP2/Grb2 signaling pathways. Cell Death Dis. 2022;13:472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ding LW, Sun QY, Lin DC, Chien W, Hattori N, Dong XM, et al. LNK (SH2B3): paradoxical effects in ovarian cancer. Oncogene. 2015;34:1463–74.

    Article  CAS  PubMed  Google Scholar 

  23. Fasouli ES, Katsantoni E. JAK-STAT in early hematopoiesis and leukemia. Front Cell Dev Biol. 2021;9:669363.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Putri A, Rinaldi I, Louisa M, Koesnoe S. The role of STAT5 in tyrosine kinase inhibitor (IMATINIB) resistance in CML patients. Acta Med Indones. 2019;51:348–52.

    PubMed  Google Scholar 

  25. Maurer B, Kollmann S, Pickem J, Hoelbl-Kovacic A, Sexl V. STAT5A and STAT5B-twins with different personalities in hematopoiesis and leukemia. Cancers (Basel). 2019;11:1726.

    Article  CAS  PubMed  Google Scholar 

  26. Wu CJ, Sundararajan V, Sheu BC, Huang RY, Wei LH. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: mechanism and therapeutic opportunity. Cancers (Basel). 2019;12:24.

    Article  PubMed  Google Scholar 

  27. Holdreith N, Lee G, Chandra V, Salinas CS, Nicholas P, Olson TS, et al. LNK (SH2B3) inhibition expands healthy and Fanconi anemia human hematopoietic stem and progenitor cells. Blood Adv. 2022;6:731–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen Y, Fang F, Hu Y, Liu Q, Bu D, Tan M, et al. The polymorphisms in LNK gene correlated to the clinical type of myeloproliferative neoplasms. PLoS ONE. 2016;11:e154183.

    Google Scholar 

  29. Pardanani A, Lasho T, Finke C, Oh ST, Gotlib J, Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia. 2010;24:1713–8.

    Article  CAS  PubMed  Google Scholar 

  30. Gery S, Gueller S, Chumakova K, Kawamata N, Liu L, Koeffler HP. Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders. Blood. 2007;110:3360–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, et al. Lnk regulates integrin alphaIIbbeta3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. J Clin Investig. 2010;120:179–90.

    Article  CAS  PubMed  Google Scholar 

  32. Tefferi A, Lasho TL, Guglielmelli P, Finke CM, Rotunno G, Elala Y, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv. 2016;1:21–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379:1416–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rontauroli S, Carretta C, Parenti S, Bertesi M, Manfredini R. Novel molecular insights into leukemic evolution of myeloproliferative neoplasms: a single cell perspective. Int J Mol Sci. 2022;23:15256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pileri A, Pellegrini C, Agostinelli C, Grandi V, Patrizi A, Zinzani PL, et al. Erythroderma and non-Hodgkin T-cell lymphoma: what else, apart from Mycosis Fungoides and Sezary syndrome?. Eur J Dermatol. 2017;27:49–53.

    Article  PubMed  Google Scholar 

  36. Miyashiro D, Souza B, Torrealba MP, Manfrere KCG, Sato MN, Sanches JA. The role of tumor microenvironment in the pathogenesis of sezary syndrome. Int J Mol Sci 2022;23: 936.

  37. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity. 2011;35:792–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Luwor RB, Baradaran B, Taylor LE, Iaria J, Nheu TV, Amiry N, et al. Targeting Stat3 and Smad7 to restore TGF-beta cytostatic regulation of tumor cells in vitro and in vivo. Oncogene. 2013;32:2433–41.

    Article  CAS  PubMed  Google Scholar 

  39. Xu Q, Chen S, Hu Y, Huang W. Landscape of immune microenvironment under immune cell infiltration pattern in breast cancer. Front Immunol. 2021;12:711433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zeng R, Wu H, Qiu X, Zhuo Z, Sha W, Chen H. Predicting survival and immune microenvironment in colorectal cancer: a STAT signaling-related signature. QJM. 2022;115:596–604.

    Article  CAS  PubMed  Google Scholar 

  41. Zhu M, Li S, Cao X, Rashid K, Liu T. The STAT family: key transcription factors mediating crosstalk between cancer stem cells and tumor immune microenvironment. Semin Cancer Biol. 2023;88:18–31.

    Article  CAS  PubMed  Google Scholar 

  42. Savani M, Dulery R, Bazarbachi AH, Mohty R, Brissot E, Malard F, et al. Allogeneic haematopoietic cell transplantation for myelofibrosis: a real-life perspective[J]. Br J Haematol. 2021;195:495–506.

    Article  CAS  PubMed  Google Scholar 

  43. McLornan DP, Hernandez-Boluda JC, Czerw T, Cross N, Joachim Deeg H, Ditschkowski M, et al. Allogeneic haematopoietic cell transplantation for myelofibrosis: proposed definitions and management strategies for graft failure, poor graft function and relapse: best practice recommendations of the EBMT Chronic Malignancies Working Party. Leukemia. 2021;35:2445–59.

    Article  PubMed  Google Scholar 

  44. Hernandez-Boluda JC, Pereira A, Kroger N, Beelen D, Robin M, Bornhäuser M, et al. Determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation. Leukemia. 2021;35:215–24.

    Article  PubMed  Google Scholar 

  45. Bryan JC, Verstovsek S. Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib. Cancer Chemother Pharm. 2016;77:1125–42.

    Article  CAS  Google Scholar 

  46. Greenfield G, McPherson S, Mills K, McMullin MF. The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms. J Transl Med. 2018;16:360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tan J, Chow YP, Zainul AN, Chang KM, Selvaratnam V, Tumian NR, et al. Analysis of genetic variants in myeloproliferative neoplasms using a 22-gene next-generation sequencing panel. BMC Med Genom. 2022;15:10.

    Article  CAS  Google Scholar 

  48. Nielsen FC, van Overeem HT, Sorensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer. 2016;16:599–612.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 32000622, 82103184, 81672632, and 81972312), the Science and Technology Innovation Program of Hunan Province of China (Grant No. 2022RC1165), the Natural Science Foundation of Hunan Province of China (Grant Nos. 2021JJ40720, 2021JJ30912, 2021JJ40052,2022JJ40579, and 2023JJ30895), the Research Project of Health Commission of Hunan Province of China (Grant No. 202202085572), Key Research and Development Plan Projects in Hunan Province of China (Grant No. 2022SK2005), and the College Students’ Innovative Entrepreneurial Training Plan Program of Hunan Province of China (Grant No. S2022105330463), The graduate student independent exploration and innovation project of Central South University (2021zzts0081). This work was supported in part by the High Performance Computing Center of Central South University.

Author information

Author notes

  1. These authors contributed equally: Shubing Zhang, Jinhua Yan.

Authors and Affiliations

  1. Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, Hunan, P. R. China

    Shubing Zhang & Jinhua Yan

  2. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, 410013, Changsha, Hunan, P. R. China

    Shubing Zhang

  3. School of Biomedical Science, Hunan University, 410013, Changsha, Hunan, P. R. China

    Lan He

  4. Department of Hematology, Central South University, Xiangya Hospital, 410013, Changsha, Hunan, P. R. China

    Zhiping Jiang

  5. Xiangya Hospital, Central South University, National Clinical Research Center for Geriatric Disorders, 410013, Changsha, Hunan, P. R. China

    Zhiping Jiang

  6. Hunan Hematology Oncology Clinical Medical Research Center, 410013, Changsha, Hunan, P. R. China

    Zhiping Jiang

  7. Department of Biomedical Informatics, School of Life Sciences, Central South University, 410013, Changsha, Hunan, P. R. China

    Hao Jiang

Authors
  1. Shubing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinhua Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiping Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SZ was responsible for conceptualization, investigation, formal analysis, writing the original draft, review and editing the manuscript. JY was responsible for investigation, creation of the figures, writing the original draft, review and editing the manuscript. LH performed the experiments. ZJ was responsible for conceptualization and reviewed and edited the manuscript. HJ was responsible for conceptualization, formal analysis, creation of the figures, review and editing of the manuscript, and funding acquisition.

Corresponding authors

Correspondence to Zhiping Jiang or Hao Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, S., Yan, J., He, L. et al. STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient. Cancer Gene Ther 31, 484–494 (2024). https://doi.org/10.1038/s41417-023-00719-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-023-00719-7

Search

Advanced search

Quick links