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Mutations of the AML1 gene in acute myeloid leukemia of FAB types M0 and M7
Author(s) -
Langabeer Stephen E.,
Gale Rosemary E.,
Rollinson Sara J.,
Morgan Gareth J.,
Linch David C.
Publication year - 2002
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.10031
Subject(s) - haploinsufficiency , myeloid leukemia , leukemia , biology , runx1 , cancer research , loss of heterozygosity , mutation , genetics , myeloid , pathogenesis , gene , loss function , acute megakaryoblastic leukemia , haematopoiesis , allele , transcription factor , immunology , stem cell , phenotype
The AML1 gene encodes a transcription factor that, together with its heterodimeric partner CBFB, regulates a number of target genes that are essential for normal hemopoiesis. In acute myeloid leukemia (AML), AML1 is disrupted not only by chromosomal translocations but also by mutations in the runt domain, which binds both DNA and CBFB. Acquired mutations have been described predominantly in the AML FAB type M0. To date, most patients appear to have biallelic disease, suggesting a complete lack of normal AML1 function. Inherited loss of function mutations thought to lead to haploinsufficiency also have been described in patients who have a familial disorder with predisposition to AML (FPD/AML), indicating the role of AML1 in megakaryopoiesis. Using single‐strand conformation polymorphism analysis, we studied the AML1 runt domain in 41 patients with M0 AML and identified potentially pathologic mutations in five (12%). Biallelic disease could be confirmed in only one patient, using loss of heterozygosity studies. At least three of the mutations would lead to truncated proteins similar to those reported in FPD/AML, suggesting that haploinsufficiency plays a role in the pathogenesis of this minimally differentiated type of leukemia. The incidence of acquired mutations in AML patients with acute megakaryoblastic leukemia (FAB type M7) was the same as that reported in other non‐M0 patients, with only one mutation detected in 20 (5%) patients studied. © 2002 Wiley‐Liss, Inc.