Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia

Abstract

BackgroundChronic myelomonocytic leukemia (CMML) is a myeloid neoplasm classified in the myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category. Molecular abnormalities are reported in about 90 % of patients with CMML. ASXL1 and SETBP1 mutations, but not TET2 or SFRS2 mutations are reported to be associated with prognosis.MethodsWe studied frequency of TET2, SRSF2, ASXL1 and SETBP1 mutations in 145 patients with CMML using Sanger sequencing, and determined the prognostic factors for OS. We also identified the predictive value of ASXL1 mutations (frameshift and nonsense mutations) through comparing the Mayo Prognostic Model with the Mayo Molecular Model.ResultsForty-seven (32 %) had a mutation in TET2, 42 (29 %), a mutation in SRSF2, 65 (45 %), a mutation (nonsense and frame-shift) in ASXL1 and 26 (18 %), a mutation in SETBP1. Significant variables in multivariable analysis of survival included ASXL1 (HR = 1.99 [1.20–3.28]; P = 0.007), hemoglobin <100 g/L (HR = 2.42 [1.40–4.19]; P = 0.002) and blood immature myeloid cells (IMCs) (HR = 2.08 [1.25–3.46]; P = 0.005). When our patients were analyzed using the Mayo Prognostic Model median OS were not reached, 26 months and 15 months (P = 0.014). An analysis using the Mayo Molecular Model identified 4 cohorts with median OS of not reached, 70 months, 26 months and 11 months (P < 0.001). Data fitting using our patients suggest the Molecular Mayo Model has significantly higher survival predictive power compared with Mayo Prognostic Model (P < 0.001, −2 log-likelihood ratios of 538.070 and 552.260).ConclusionsThere were high frequencies of mutations in TET2, SRSF2, ASXL1 and SETBP1 in patients with CMML. With the addition of ASXL1 frameshift and nonsense mutations, the Mayo Molecular Model fitted better than Mayo Prognostic Model of our patients.

Somatic SETBP1 mutations in myeloid neoplasms

“…These findings suggest that SETBP1 mutations play a main role in secondary leukemogenesis as later subclonal events, presumably required for antecedent disease initiation by other primary genetic defects [45]. Sanger sequencing could not sufficiently detect SETBP1 mutations in CMML [39,46] or therapy-related myeloid neoplasms [43], hence is not likely to be recommended to detect typical small clones with the mutation. In cases with another MDS/MPN subtype, refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), SETBP1 mutation was also frequently observed (13%) [47].…”

How I investigate chronic myelomonocytic leukemia

“…SF3B1 and U2AF1 mutations recur in MD‐CMML variant, whilst mutations affecting the RAS pathway, RUNX1, and EZH2 are more common in the MP‐CMML variant . Of these, ASXL1 mutations are of particular importance as they have been correlated with adverse prognosis and a poor overall survival . Such mutational profile may have clinical repercussions in the near future, as target molecules targeting the RAS signaling pathway and the spicing machinery are under investigation …”

“…57,58 Of these, ASXL1 mutations are of particular importance as they have been correlated with adverse prognosis and a poor overall survival. 59,60 Such mutational profile may have clinical repercussions in the near future, as target molecules targeting the RAS signaling pathway and the spicing machinery are under investigation. [4][5][6] NPM1 mutations occur in around 5% of CMML.…”

TET2 mutations were predictive of inferior prognosis in the presence of ASXL1 mutations in patients with chronic myelomonocytic leukemia

“…Somatic mutations have been detected in about 90% of patients with chronic myelomonocytic leukemia (CMML) and the most frequent mutations occur in epigenetic regulators (TET2, 40-60%), histone modification and chromatin regulation (ASXL1, 30-50%), splicing components (SRSF2, 30-50%), transcription factors (RUNX1, 10-20%), and signaling regulator genes (SETBP1, 10-20%) (1)(2)(3)(4)(5). In proximately, over 40% CMML patients have at least two mutations (3,5,6).…”

“…In proximately, over 40% CMML patients have at least two mutations (3,5,6). The diverse combinations of mutations detected in CMML suggest multi-step pathogenesis of the disease in some cases.…”