Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

Abstract

Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

“…In addition, a construct containing a point mutation within the RHD of TEL-AML1 was generated (MSCV-R201Q). R201Q is the most frequent mutation in the RHD of AML1 in human patients, found in familial platelet disorder with predisposition to AML (Song et al, 1999), AML (Preudhomme et al, 2000) and cleidocranial dysplasia (Quack et al, 1999;Zhou et al, 1999;Otto et al, 2002;Yoshida et al, 2002). Conservative mutation of this amino acid, at the corresponding position in mouse AML1 (R174), reduces the affinity of the AML1 RHD domain for DNA by 1000-fold, without disrupting heterodimerization with the corebinding factor (CBF)b cofactor or perturbing the RHD fold (Li et al, 2003).…”

“…It was suggested that this would result in an increased pool of progenitor cells in which the accumulation of further mutations may lead to leukemia. Indeed haploinsufficiency of AML1 and loss-of-function point mutations in AML1 have been both implicated in predisposition to myeloid leukemia (Osato et al, 1999;Song et al, 1999). If TEL-AML1 interferes with AML1 activity it is likely that this would result in increased progenitor generation and predisposition to leukemia.…”

Accommodating haploinsufficient tumour suppressor genes in Knudson's model

“…Figure 1b refers to Rb-de®cient mice expressing various levels of human RB from a transgene: whereas less than 20% of the normal haploid level seems to su ce to suppress tumorigenicity in the mouse pituitary gland, approximately 100% is needed to allow development of the embryo (Chang et al, 1993). A third pattern may be exempli®ed by Cbfa2 (Figure 1c), one copy of which is su cient for development (Okuda et al, 1996), though not for full megakaryopoiesis and possibly not for tumour suppression (Song et al, 1999;Wang et al, 1996). Figure 1 highlights the fact that there will be selective pressure for loss of function of both alleles in each case.…”

“…There are reports in the literature for several tsg, namely Nf1 (Jacks et al, 1994), p27 Kip1 (Pietenpol et al, 1995), Msh2 (de Wind et al, 1998, Pten (Podsypanina et al, 1999), Tsc2 (Kobayashi et al, 1999), CBFA2 (Song et al, 1999) and p53 (Nigro et al, 1989;Mulligan et al, 1990;Davido et al, 1991;Sedlacek et al, 1998), of tumours retaining a single possibly active allele. But by far the strongest evidence of this kind is for haploinsu ciency of p53 and p27 Kip1 in hemizygous mice, where the potential complication of dominant negative mutations has been excluded (Venkatachalam et al, 1998;Fero et al, 1998).…”

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

“…Three genes have been causally linked to leukaemia susceptibility: RUNX1, CEBPA and GATA2. [1][2][3] In addition, TERC and TERT mutations have also been reported in patients of familial MDS/ AML. 4 However, familial AML is a genetically heterogeneous disorder, and the culprit genes in the majority of AML pedigrees remain obscure.…”