Genome wide molecular analysis of minimally differentiated acute myeloid leukemia.
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.


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.
Department of Toxicogenetics, Leiden University Medical Center, PO box 9600, Postzone S4-P, 2300 RC Leiden, the Netherlands.
Fernando P G
FP
Silva
Inês
I
Almeida
Bruno
B
Morolli
Geeske
G
Brouwer-Mandema
Hans
H
Wessels
Rolf
R
Vossen
Harry
H
Vrieling
Erik W A
EW
Marijt
Peter J M
PJ
Valk
Hanneke C
HC
Kluin-Nelemans
Wolfgang R
WR
Sperr
Wolf-Dieter
WD
Ludwig
Micheline
M
Giphart-Gassler
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000145:classification* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human