Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in >80% of patients with TET2 and EZH2 being of high prognostic relevance

Abstract

for groups 5, 7 and 8, respectively (median event-free survival: groups 1-2: not reached; groups 3-8: 15.9, 13.5, 6.3, 16.0, 7.5 and 12.5 months (Figures 1b and c)). Thus, the OS of AML with inv(3)(q21q26)/t(3;3)(q21;q26) was similar to complex aberrant AML. Many cytogenetic studies did not specify on outcomes of AML with inv(3)(q21q26)/t(3;3)(q21;q26), but combined this subtype with other rare or unfavorable alterations. According to a recent Medical Research Council (MRC) study, the 10-year OS rate was 3% and the cumulative incidence of relapse was 89% in patients with AML and inv(3)(q21q26)/t(3;3)(q21;q26), 4 and Lugthart et al. 5 described a 5-year OS of 5.7% in these patients. Weisser et al. 8 suggested that the prognosis of patients with an inv(3)(q21q26)/t(3;3)(q21;q26) was significantly improved by allogeneic hematopoietic stem cell transplantation.In summary, the AML cohort with inv(3)(q21q26)/ t(3;3)(q21;q26) showed higher frequencies of additional cytogenetic and molecular mutations than did MDS patients. As most cases (85.3% of the total cohort) had additional cytogenetic and/or molecular genetic abnormalities, inv(3)(q21q26)/ t(3;3)(q21;q26) seems unable to induce leukemogenesis without the support of other genetic alterations. The prognosis of patients with inv(3)(q21q26)/t(3;3)(q21;q26) is unfavorable both in MDS and in AML. Therefore, our data support to classify cases with an inv(3)(q21q26)/t(3;3)(q21;q26) as AML irrespective of blast count comparable with the WHO categories AML t(8;21) (q22;q22)/RUNX1-RUNX1T1, inv(16)(p13q22)/t16;16)(p13;q22)/ CBFB-MYH11 or t(15;17)(q22;q12)/PML-RARA. Cooperation with RAS-activating mutations is frequent in myeloid malignancies with an inv(3)(q21q26)/t(3;3)(q21;q26). Developing this and published data to a perspective targeting the RAS pathway might be a promising therapeutic approach in this AML subtype. Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in 480% of patients with TET2 and EZH2 being of high prognostic relevance Conflict of interest

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

“…Thus far, in CMML loss of function gene mutations involving ASXL1 and EZH2 have been associated with poor outcome [10,11]. Recently, mutations involving the spliceosome machinery have been described in patients with myeloid neoplasms, including MDS, CMML, MPN, and AML [12,13,17,18,30].…”

“…These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.…”

“…These include mutations involving; RUNX1 [3], IDH1, and IDH2 [4], KRAS and NRAS [5], CBL [6], JAK2 [7], TET2 [8], DNMT3A [9], ASXL1 [10], UTX [9], and EZH2 [9]. Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.…”

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories

“…1,2 It has become apparent that NGS platforms will have practical applications in clinical diagnostics and applications, such as detection of EGFR mutations in lung adenocarcinoma, 3 characterizing RAS and methylation pathway alterations in myeloproliferative diseases and myeloid leukemias, [4][5][6][7] or high-resolution, high-throughput human leukocyte antigen genotyping have been developed. 8,9 Thus far, limited data are available on the technical performance of amplicon deep sequencing in a clinical diagnostic setting.…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…Recently, CMML has been associated with somatic mutations in a growing number of genes. Somatic frameshift or point mutations are frequently found in CBL, TET2, EZH2, ASXL1, and the RAS pathway, while, in particular, alterations in TET2 and EZH2 have been associated with a poor prognosis [Grossmann et al, 2011]. SNP-based array analysis has identified large stretches of CNLOH regions as the sole genomic abnormality (Fig.…”