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.

Clinicopathologic spectrum of myeloid neoplasms with concurrent myeloproliferative neoplasm driver mutations and SRSF2 mutations

Abstract

Myeloproliferative neoplasms (MPNs) are frequently associated with classic driver mutations involving JAK2, MPL or CALR. SRSF2 is among the most frequently mutated splicing genes in myeloid neoplasms and SRSF2 mutations are known to confer a poor prognosis in patients with MPNs. In this study, we sought to evaluate the clinicopathologic spectrum of myeloid neoplasms harboring concurrent MPN-driver mutations and SRSF2 mutations. The study cohort included 27 patients, 22 (82%) men and five (19%) women, with a median age of 71 years (range, 51–84). These patients presented commonly with organomegaly (n = 15; 56%), monocytosis (n = 13; 48%), morphologic dysplasia (n = 11; 41%), megakaryocytic hyperplasia and/or clustering (n = 10; 37%) and bone marrow fibrosis >MF-1 (17/22; 77%). About one third of patients either initially presented with acute myeloid leukemia (AML) or eventually progressed to AML. Eighteen (68%) patients had a dominant clone with SRSF2 mutation and nine (33%) patients had a dominant clone with a classic MPN-associated driver mutation. Our data suggest that the presence of an SRSF2 mutation preceding the acquisition of a MPN driver mutations is not a disease-defining alteration nor is it restricted to any specific disease entity within the spectrum of myeloid neoplasms. In summary, patients with myeloid neoplasms associated with concurrent SRSF2 and classic MPN driver mutations have clinical and morphologic features close to that of classic MPNs often with frequent dysplasia and monocytosis.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Detailed spectrum of disease classification and molecular characterization of study group.
Fig. 2: Examples of spectrum of morphologic features in the study group.
Fig. 3: Mutational landscape in the study group, subclassified per disease group.
Fig. 4: Clonal dominance in relation to disease subclassification.
Fig. 5

Data availability

All data are available upon request.

References

  1. Kvasnicka, H. M., Thiele, J., Orazi, A., Horny, H. P. & Bain, B. J. Myeloproliferative neoplasm, unclassifiable. In: S.H. Swerdlow et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 57–59 (IARC Lyon, 2017).

  2. Orazi, A., Bennett, J. M., Bain, B. J., Baumann, I., Thiele, J., Bueso-Ramos, C. et al. Myelodysplastic I myeloproliferative neoplasm, unclassifiable. In: S.H. Swerdlow et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 95–96 (IARC: Lyon, 2017).

  3. Grinfeld, J., Nangalia, J., Baxter, E. J., Wedge, D. C., Angelopoulos, N., Cantrill, R. et al. Classification and Personalized Prognosis in Myeloproliferative Neoplasms. New England Journal of Medicine 379, 1416–1430 (2018).

  4. Papaemmanuil, E., Gerstung, M., Malcovati, L., Tauro, S., Gundem, G., Van Loo, P. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627; quiz 3699 (2013).

  5. Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011).

  6. Kim, E., Ilagan, J. O., Liang, Y., Daubner, G. M., Lee, S. C., Ramakrishnan, A. et al. SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell 27, 617–630 (2015).

  7. Patnaik, M. M., Lasho, T. L., Finke, C. M., Hanson, C. A., Hodnefield, J. M., Knudson, R. A. et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 88, 201–206 (2013).

  8. Makishima, H., Visconte, V., Sakaguchi, H., Jankowska, A. M., Abu Kar, S., Jerez, A. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119, 3203–3210 (2012).

  9. Wu, S. J., Kuo, Y. Y., Hou, H. A., Li, L. Y., Tseng, M. H., Huang, C. F. et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood 120, 3106–3111 (2012).

  10. Federmann, B., Abele, M., Rosero Cuesta, D. S., Vogel, W., Boiocchi, L., Kanz, L. et al. The detection of SRSF2 mutations in routinely processed bone marrow biopsies is useful in the diagnosis of chronic myelomonocytic leukemia. Hum Pathol 45, 2471–2479 (2014).

  11. Vannucchi, A. M., Lasho, T. L., Guglielmelli, P., Biamonte, F., Pardanani, A., Pereira, A. et al. Mutations and prognosis in primary myelofibrosis. Leukemia 27, 1861–1869 (2013).

  12. Zhang, S. J., Rampal, R., Manshouri, T., Patel, J., Mensah, N., Kayserian, A. et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 119, 4480–4485 (2012).

  13. Chapman, J., Geyer, J. T., Khanlari, M., Moul, A., Casas, C., Connor, S. T. et al. Myeloid neoplasms with features intermediate between primary myelofibrosis and chronic myelomonocytic leukemia. Mod Pathol 31, 429–441 (2018).

  14. Gur, H. D., Loghavi, S., Garcia-Manero, G., Routbort, M., Kanagal-Shamanna, R., Quesada, A. et al. Chronic Myelomonocytic Leukemia With Fibrosis Is a Distinct Disease Subset With Myeloproliferative Features and Frequent JAK2 p.V617F Mutations. Am J Surg Pathol 42, 799–806 (2018).

  15. Hu, Z., Ramos, C. E. B., Medeiros, L. J., Zhao, C., Yin, C. C., Li, S. et al. Utility of JAK2 V617F allelic burden in distinguishing chronic myelomonocytic Leukemia from Primary myelofibrosis with monocytosis. Hum Pathol 85, 290–298 (2019).

  16. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (IARC Lyon, 2017).

  17. Della Porta, M. G., Travaglino, E., Boveri, E., Ponzoni, M., Malcovati, L., Papaemmanuil, E. et al. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia 29, 66–75 (2015).

  18. Thiele, J., Kvasnicka, H. M., Facchetti, F., Franco, V., van Der Walt, J. & Orazi, A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90, 1128–1132 (2005).

  19. Khoury, J. D., Sen, F., Abruzzo, L. V., Hayes, K., Glassman, A. & Medeiros, L. J. Cytogenetic findings in blastoid mantle cell lymphoma. Hum Pathol 34, 1022–1029 (2003).

  20. McGowan-Jordan J, S. A., Schmid M. ISCN 2016: An International System for Human Cytogenomic Nomenclature (2016). (Basel: S. Karger Publishing, 2016).

  21. Ok, C. Y., Loghavi, S., Sui, D., Wei, P., Kanagal-Shamanna, R., Yin, C. C. et al. Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia. Haematologica 104, 305–311 (2019).

  22. Lee, S. C., North, K., Kim, E., Jang, E., Obeng, E., Lu, S. X. et al. Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations. Cancer Cell 34, 225-241 e228 (2018).

  23. Taylor, J., Mi, X., North, K. D., Binder, M., Penson, A., Lasho, T. L. et al. Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms. Blood https://doi.org/10.1182/blood.2020006868 (2020).

Download references

Author information

Authors and Affiliations

Authors

Contributions

M.T. and S.L. designed the study, reviewed the pathology, collected and analyzed data. J.D.K., S.A.W., S.H., P.L. C.B.R., L.J.M. collected pathology data, M.J.R., R.L. K.P.P. C.Y.O., R.K.S. collected molecular data, SHE assisted in manuscript preparation, N.P., P.B. and S.V. manages patients and collected clinical data. All authors were involved in manuscript preparation and approved the final draft.

Corresponding author

Correspondence to Sanam Loghavi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) at MD Anderson Cancer Center (MDACC) and conducted in accord with the Declaration of Helsinki. Consent is not applicable for this retrospective study.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tashakori, M., Khoury, J.D., Routbort, M.J. et al. Clinicopathologic spectrum of myeloid neoplasms with concurrent myeloproliferative neoplasm driver mutations and SRSF2 mutations. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01118-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41379-022-01118-3

Search

Quick links