Published online 22 September 2009
Haematologica, Vol 94, Issue 11, 1546-1554 doi:10.3324/haematol.2009.009324
Copyright © 2009 by Ferrata Storti Foundation
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Acute Myeloid Leukemia

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

Fernando P.G. Silva1, Inês Almeida1, Bruno Morolli1, Geeske Brouwer-Mandema2, Hans Wessels3, Rolf Vossen4, Harry Vrieling1, Erik W.A. Marijt2, Peter J.M. Valk5, Hanneke C. Kluin-Nelemans2,6, Wolfgang R. Sperr7, Wolf-Dieter Ludwig8, Micheline Giphart-Gassler1

1 Department of Toxicogenetics
2 Department of Hematology
3 Department of Clinical Cytogenetics
4 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
5 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
6 Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands
7 Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
8 Robert-Rössle-Clinic at the HELIOS Clinic Berlin-Buch, Department of Hematology, Oncology, and Tumor Immunology, Berlin, Germany

Correspondence: Micheline Giphart-Gassler, Department of Toxicogenetics, Leiden University Medical Center, PO box 9600, Postzone S4-P, 2300 RC Leiden, the Netherlands. E-mail:m.giphart-gassler{at}lumc.nl

Background: Minimally 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 Methods: We performed whole genome single nucleotide polymorphism analysis and extensive molecular analysis in a cohort of 52 patients with minimally differentiated acute myeloid leukemia.

Results: Many 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.

Conclusions: Our results suggest that in patients without RUNX1 mutation, several other molecular aberrations, separately or in combination, contribute to a common minimally differentiated phenotype.

Key words: AML-M0, loss of heterozygosity (LOH), RUNX1, acute myeloid leukemia.




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F. P. G. Silva, S. M. A. Swagemakers, C. Erpelinck-Verschueren, B. J. Wouters, R. Delwel, H. Vrieling, P. van der Spek, P. J. M. Valk, and M. Giphart-Gassler
Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status
Blood, October 1, 2009; 114(14): 3001 - 3007.
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