SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

“…Further analysis revealed SETBP1 mutations in unclassified of MDS/MPN (10%), CMML (4%), and one of four cases of CNL, but not in a wide range of other hematologic malignancies or cell lines of lymphoma and solid tumors [66]. Other investigators sought to reproduce these findings and reported SETBP1 mutation frequencies of up to 32, 7, 3, 2, and 2.5% in aCML, CMML, PMF, MDS, and secondary AML, respectively [67][68][69][70]. An association with high leukocyte counts and an independent detrimental effect on prognosis was confirmed in most but not all series.…”

CMML: Clinical and molecular aspects

“…Finally, mutations in the transcription factor RUNX1 are seen in 10-15% of cases, notably in patients with thrombocytopenia. Mutations in SETBP1 are also found in ~5% of CMML cases, and these cases often harbor a phenotype close to that of aCML, with predominant granulocytic over monocytic hyperplasia [15]. Finally, an intriguing feature of CMML is the scarcity of mutations in TP53 in contrast to other myeloid neoplasms.…”

“…The formal inclusion of the >10% WBC rule in the diagnosis of CMML better helps delineating it from atypical Chronic Myeloid Leukemia (aCML) or unclassified MDS/ MPN (MDS/MPNu), where absolute monocytosis is often present but where granulocytic hyperplasia is predominant, though from a molecular perspective, it is likely that a continuum exists between these entities [15,16], raising questions on genotype/phenotype correlates in myeloid neoplasms [17]. The WHO recommends stratifying CMML into three groups based on bone marrow and peripheral blood blast count: CMML-0 [blasts <2% in peripheral blood (PB) and <5% in bone marrow (BM)], CMML-1 (2-4% in PB, 5-9% in BM) and CMML-2 (5-19% in PB, 10-19% in BM, or presence of Auer rods).…”

“…If ASXL1 RUNX1 and SETBP1 mutations appear detrimental in most series [3,15,[55][56][57], the prognosis of TET2, SRSF2 and RAS/CBL mutations seems more controversial, perhaps because of interactions with other gene mutation status [58], clinical variables such as myeloproliferative features, or with treatment. Finally, rare mutations such as those in EZH2 or DNMT3A are probably of poor prognosis [59,60], but only very large series will allow to incorporate them into molecular stratifications.…”

SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms

“…Among these, SET binding protein 1 (SETBP1) has been reported as frequently mutated in chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), secondary acute myeloid leukemia (s-AML) and in distinct subgroups of primary myelodysplastic syndromes (MDS), such as refractory anemia with excess of blasts (RAEB1 and RAEB2). [4][5][6][7][8][9][10] SETBP1 germ-line mutations are responsible for the Schinzel-Giedion syndrome (SGS), originally identified by Albert Schinzel and Andreas Giedion in 1978. It is a congenital disease characterized by a higher prevalence of tumors, severe mid-face hypoplasia, congenital heart defect and skeletal anomalies.…”