CEBPA double‐mutated acute myeloid leukaemia harbours concomitant molecular mutations in 76·8% of cases with TET2 and GATA2 alterations impacting prognosis

Abstract

SummaryAcute myeloid leukaemia (AML) with CEBPA mutations is listed as a provisional entity in the current World Health Organization classification. A difference in clinical outcome between single-(sm) and double-mutated (dm) cases has been reported, whereupon CEBPAdm cases were shown to be associated with better overall survival (OS). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPAdm has not been assessed until now with exception of GATA2 mutations. Here, we investigated a cohort of 95 AML CEBPAdm cases for concomitant mutations. TET2 was found to be most frequently mutated (34Á0%) gene, followed by GATA2 (21Á0%), WT1 (13Á7%), DNMT3A (9Á6%), ASXL1 (9Á5%), NRAS (8Á4%), KRAS (3Á2%), IDH1/2 (6Á3%), FLT3-internal tandem duplication (6Á3%), FLT3-tyrosine kinase domain (2Á1%), NPM1 (2Á1%), and RUNX1 (1/94). Patients harbouring additional mutations in the TET2 gene showed significantly worse OS than TET2 wild-type cases (P = 0Á035), whereas GATA2-mutated patients showed improved OS (P = 0Á032). Serial analyses were performed for 39 CEBPAdm cases with concomitant mutations. Here, we observed that CEBPA mutations present the primary pathogenetic event in the majority of cases (76Á9%). Further, a distinct gene expression profile (GEP) was confirmed for CEBPAdm versus CEBPAsm or CEBPA wild-type cases while no significant changes in GEP were observed related to additional mutations within the CEBPAdm AML.

Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations

“…However, we confirmed no prognostic impact of GATA2 mutations (n 5 25) compared to wild-type (n 5 62) in our cohort of CEBPA dm AML [8,9] (22 vs. 58 and 10 vs. 16) with a trend similar of better outcome in CEBPA dm with GATA2 mutations compared to wild-type [5,6] (18 vs. 62). Furthermore, our study provided first evidence that homozygous CEPBA mutations have a similar gene expression signature as CEPBA dm and thus may be considered as equivalent.…”

“…Many ITP patients, particularly patients with anti-GP Ib-IX autoantibodies, do not respond to conventional treatments such as steroids, intravenous immunoglobulins, or splenectomy [4][5][6][7][8]. Also the role of new therapies like thrombopoietin agonist are unclear and not without risks [9].…”

“…Oseltamivir phosphate, the ethyl ester prodrug of oseltamivir carboxylate that conventionally serves as an antiviral sialidase inhibitor, has been prescribed worldwide for the treatment of patients with influenza [10]. Sporadic case reports showed a significant response on platelet count in patients with chronic ITP who were treated with oseltamivir [6,11].…”

“…Recent studies associated GATA2 mutations with CEBPA double mutations and improved overall survival (OS) [5,6]. In contrast, another study failed to show any impact thereof on OS [1].…”

Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors

“…13,14 Gene expression studies have shown that CEBPA bi samples, but not specimens with CEBPA monoallelic mutations, have a distinctive gene expression profile (GEP), [15][16][17][18] and analyses of small series indicated a possibility that this profile is shared by some atypical CEBPA bi AML. 15 Mutations in genes such as GATA2, WT1, and TET2 have been described thus far in CEBPA bi specimens, [19][20][21][22] including 6 specimens reported in The Cancer Genome Atlas cohort. 7 We previously used comparative transcriptomic approaches to report the mutational and transcriptional landscapes of MLL,…”