Abstract
Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.
Highlights
In vitro studies have shown that additional sex combs 1 gene (ASXL1) mutations enhance the de-ubiquitinase activity of the ASXL1– BAP1 (BRCA associated protein 1) complex, which cooperates with loss of TET2 to skew towards myeloid development.[11]
Twenty-seven gene panel targeted capture assays were carried out on bone marrow DNA specimens obtained at diagnosis for the following genes: TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, serine/arginine-rich splicing factor 2 (SRSF2), splicing factor 3B subunit 1 (SF3B1), ZRSR2, U2 small nuclear RNA auxiliary factor 1 (U2AF1), PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF and SETBP1
One hundred and forty-six (83%) patients were subclassified as chronic myelomonocytic leukemia (CMML)-1 and the remainder had CMML-2
Summary
Gene mutations are common (490%) in chronic myelomonocytic leukemia (CMML) and involve epigenetic regulators (TET2 ~ 60%and ASXL1 ~ 40%), spliceosome components (SRSF2 ~ 50%) and cell signaling (RAS ~ 30% and CBL ~ 15%).[1,2,3,4] Mutations involvingASXL1, TET2, RUNX1, CBL, SRSF2, RAS and IDH2 have demonstrated prognostic relevance on univariate survival analyses.[1,5,6] on multivariable analyses that have included additional CMML relevant factors, only ASXL1 mutations (frameshift and nonsense) have been shown to be prognostically detrimental.[1,2] This has led to the incorporation of ASXL1 mutations into molecular prognostic models such as the Molecular Mayo Model and the Groupe Francais des Myelodysplasies model.[1,2]TET2 mutations (chromosome 4q24) are frequent and are thought to be the driver mutations in CMML.[7]. Gene mutations are common (490%) in chronic myelomonocytic leukemia (CMML) and involve epigenetic regulators ASXL1 ~ 40%), spliceosome components (SRSF2 ~ 50%) and cell signaling (RAS ~ 30% and CBL ~ 15%).[1,2,3,4] Mutations involving. ASXL1, TET2, RUNX1, CBL, SRSF2, RAS and IDH2 have demonstrated prognostic relevance on univariate survival analyses.[1,5,6] on multivariable analyses that have included additional CMML relevant factors, only ASXL1 mutations (frameshift and nonsense) have been shown to be prognostically detrimental.[1,2] This has led to the incorporation of ASXL1 mutations into molecular prognostic models such as the Molecular Mayo Model and the Groupe Francais des Myelodysplasies model.[1,2]. In vitro studies have shown that ASXL1 mutations enhance the de-ubiquitinase activity of the ASXL1– BAP1 (BRCA associated protein 1) complex, which cooperates with loss of TET2 to skew towards myeloid development.[11]
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