1. Genome wide molecular analysis of minimally differentiated acute myeloid leukemia
- Author
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Inês Almeida, Geeske Brouwer-Mandema, Harry Vrieling, Micheline Giphart-Gassler, Peter J. M. Valk, Hans W. Wessels, Wolf-Dieter Ludwig, Wolfgang R. Sperr, Hanneke C. Kluin-Nelemans, Fernando P.G. Silva, Erik W.A. Marijt, Rolf H. A. M. Vossen, Bruno Morolli, Hematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL) more...
- Subjects
Myeloid ,Gene mutation ,POINT MUTATIONS ,Cohort Studies ,Loss of heterozygosity ,chemistry.chemical_compound ,hemic and lymphatic diseases ,TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE ,Child ,MYELODYSPLASTIC SYNDROME ,Aged, 80 and over ,ACUTE MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,Cell Differentiation ,Hematology ,Middle Aged ,INCREASED FLT3 EXPRESSION ,Leukemia, Myeloid, Acute ,Leukemia ,loss of heterozygosity (LOH) ,medicine.anatomical_structure ,ACQUIRED UNIPARENTAL DISOMY ,RUNX1 ,Child, Preschool ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,Original Article ,AML-M0 ,M0 AML ,GENE-MUTATIONS ,Adult ,Adolescent ,Biology ,acute myeloid leukemia ,Polymorphism, Single Nucleotide ,Young Adult ,POOR-PROGNOSIS ,medicine ,Humans ,AML-MO ,Aged ,Genome, Human ,Point mutation ,medicine.disease ,PTPN11 ,chemistry ,Karyotyping ,Mutation ,Cancer research - Abstract
BackgroundMinimally differentiated acute myeloid leukemia is heterogeneous in karyotype and is defined by immature morphological and molecular characteristics. This originally French-American-British classification is still used in the new World Health Organization classification when other criteria are not met. Apart from RUNX1 mutation, no characteristic molecular aberrations are recognized.Design and MethodsWe performed whole genome single nucleotide polymorphism analysis and extensive molecular analysis in a cohort of 52 patients with minimally differentiated acute myeloid leukemia.ResultsMany recurring and potentially relevant regions of loss of heterozygosity were revealed. These point towards a variety of candidate genes that could contribute to the pathogenesis of minimally differentiated acute myeloid leukemia, including the tumor suppressor genes TP53 and NF1, and reinforced the importance of RUNX1 in this leukemia . Furthermore, for the first time in this minimally differentiated form of leukemia we detected mutations in the transactivation domain of RUNX1. Mutations in other acute myeloid leukemia associated transcriptions factors were infrequent. In contrast, FLT3, RAS, PTPN11 and JAK2 were often mutated. Irrespective of the RUNX1 mutation status, our results show that RAS signaling is the most important pathway for proliferation in minimally differentiated acute myeloid leukemia. Importantly, we found that high terminal deoxynucleotidyl transferase expression is closely associated with RUNX1 mutation, which could allow an easier diagnosis of RUNX1 mutation in this hematologic malignancy.ConclusionsOur results suggest that in patients without RUNX1 mutation, several other molecular aberrations, separately or in combination, contribute to a common minimally differentiated phenotype. more...
- Published
- 2009