Identification of a Subgroup of Biphenotypic Myeloid/T-Cell Acute Leukemias with a CEBPA-Mutant Gene Expression Profile, Frequent CEBPA Promoter Hypermethylation and NOTCH1 Mutations
| Autor: | Dennis Tielemans, Bas J. Wouters, Claudia A.J. Erpelinck-Verschueren, Ruud Delwel, Peter J. M. Valk, Bob Löwenberg, Warren S. Pear, Irene Louwers, Daniel G. Tenen, Anton W. Langerak |
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| Rok vydání: | 2006 |
| Předmět: | |
| Zdroj: | Blood. 108:2237-2237 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Recently, gene expression profiling has allowed the identification of specific molecular signatures of established as well as novel subgroups of acute myeloid leukemia (AML). CEBPA mutations are observed in ~10% of AML. In a gene expression profiling study of 285 AML cases, we previously found two distinct clusters consisting of almost all specimens with CEBPA mutations, i.e. cluster #15 and cluster #4. In cluster #4, only 9 out of 15 cases were CEBPA mutant. Thus, this cluster contained 6 patients with a highly similar expression signature, but without CEBPA mutations. We wished to investigate whether these cases represent a previously unidentified subgroup of leukemias. All 6 cases appeared morphologically immature (FAB-M0 or M1) and did not carry any of the common genetic aberrations. Supervised array expression analysis revealed CEBPA to be among the most highly downregulated genes in these 6 cases, which was associated with CEBPA CpG promoter hypermethylation in 4/6. None of the CEBPA mutant cases or a random selection of 10 AML cases from other clusters exhibited CEBPA promoter methylation. Strikingly, several T-cell related genes, e.g. CD7, CD3D, IL7R and T-cell receptor delta locus, appeared significantly overexpressed in these cases. Multicolor flowcytometry demonstrated high expression of CD34 and combinations of myeloid (e.g. CD13, CD33, CD117 and/or myeloperoxidase) as well as T-lymphoid (CD7, CD3, TdT) lineage markers on all six. Expression of T-cell markers correlated with T-cell receptor rearrangements in 4/6 cases. Other highly expressed genes in these biphenotypic acute leukemias included NOTCH1 and its recently identified target gene TRIB2. Sequencing analysis demonstrated putatively activating NOTCH1 mutations in three out of six samples, as described previously in T-cell acute lymphoblastic leukemia (T-ALL). The remaining 3 cases and 25 control AMLs, including all CEBPA mutant cases, did not demonstrate any NOTCH1 mutation. Finally, based on this first cohort of patients, we determined the minimal number of probe sets accurately predicting cluster #4 biphenotypic cases, and identified eight probe sets, including those for T-cell receptor delta/alpha locus. Applying this predictor set to an independent new cohort of 272 AML cases, an identical subgroup of another 6 AML patients with frequent NOTCH1 mutations and CEBPA promoter hypermethylation could be identified. Available clinical data suggested an adverse prognosis of this type of leukemia. In conclusion, we identified a subgroup of biphenotypic acute leukemias characterized by a CEBPA mutant gene expression profile, frequent CEBPA promoter hypermethylation, and frequent NOTCH1 mutations. To our knowledge, this is the first report to describe NOTCH1 mutations in leukemia other than T-ALL. |
| Databáze: | OpenAIRE |
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