Mast cell mutations: SRSF2 in SM-AHNMD

SRSF2 is a splicing protein, which means it is involved in cutting RNA so that a gene makes the correct protein. SRSF2 mutations at position 95 (p95) have been found in 24-37% of SM patients. In nearly all cases, this mutation is found in patients that have SM-AHNMD. SRSF2 mutations at p95 are associated with myelodysplastic syndromes, leukemias and other hematologic diseases, including mastocytosis. After CKIT D816V mutation, it is the most common mutation found in systemic mastocytosis patients.

SRSF2 mutation occurs early in disease. One study indicates that it occurs in the time period between the initial TET2 mutation and the initial CKIT D816V mutation. Like TET2, it may predispose progenitor cells to develop subsequent mutations that cause disease. Patients with SRSF2 mutations are more likely to also have a TET2 mutation, and even more likely to have a mutation affecting another gene with epigenetic activity. SRSF2 alone does not drive neoplastic behavior in mast cells. SRSF2 has been found in patients without the CKIT mutation.

Importantly, SFSR2 is strongly associated with patients who develop SM-AHNMD. One study with a cohort of 72 patients with various forms of mastocytosis, including clonal MCAS (monoclonal mast cell activation syndrome) found that of 17 SM-AHNMD patients, 15 (88%) were positive for SFSR2 mutation. The associated conditions included AML, CMML, MDS, MSD (AREB), MPN, MPN/MDS and Waldenstrom’s macroglobunemia. SRSF2 mutations are not associated with any specific AHNMD and it does not predict survival time. This cohort included three patients who tested positive for the mutation but developed an AHNMD later in the study.

In SM-AHNMD patients, the SRSF2 mutations were found in both mast cells and monocytes in the bone marrow. This indicates that the mutation may cause transformation in both disease portions: SM and the AHNMD.



Hanssens K., et al. SRSF2-P95 Hotspot Mutation is Highly Associated with Advanced Forms of Mastocytosis and Mutations in Epigenetic Regulator Genes. Haematologica 2013 [Epub ahead of print.]

Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.

Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.

3 Responses

  1. Debbie Stern January 13, 2016 / 8:35 pm

    I hope you can help me. I have been ill for 8 years …possible neuroendocrine tumor, anemia, told by Dr. Castels I have “secondary mast cell disorder” .
    My heme/onc ran a” myeloid malignancy panel” on a bmb that was over 2 year old. It came out with SRSF2 c.284C>A, p.Pro95His (NM_003016.4).
    Questions..Could my secondary Mast Cell Disorder cause this? Rare mast cells were highlighted my bmb. is my study accurate since it was done on a 2 year old bmb sample? Doesn’t this panel have to be run on a fresh bmb sample? My hemoglobin is around 10.9, my bmb that the study was done on was normal??
    My wbc are normal or sometimes very slightly low; platelets normal…I am so confused.
    My heme-onc is sending me to a Myelodysplasia Specialist as he doesn’t know for sure, what is going on….please give me your input!

    • Lisa Klimas January 13, 2016 / 9:59 pm

      Those mutations can occur in several conditions. Mast cell activation is common in myeloid malignancies (or any malignancy, for that matter). No, secondary MCAS would not cause these mutations. Rare mast cells are normal in the bone marrow. Yes, the study should be accurate. Patient samples can be used for years if they are preserved correctly. Low hemoglobin is not necessarily related to bone marrow state and it is possible that the conditions are not directly related.

Comments are closed.