Genetic Heterogeneity in Familial Acute Myelogenous Leukemia: Evidence for a Second Locus at Chromosome 16q21-23.2

Abstract

The identification of genes responsible for the rare cases of familial leukemia may afford insight into the mechanism underlying the more common sporadic occurrences. Here we test a single family with 11 relevant meioses transmitting autosomal dominant acute myelogenous leukemia (AML) and myelodysplasia for linkage to three potential candidate loci. In a different family with inherited AML, linkage to chromosome 21q22.1-22.2 was recently reported; we exclude linkage to 21q22.1-22.2, demonstrating that familial AML is a heterogeneous disease. After reviewing familial leukemia and observing anticipation in the form of a declining age of onset with each generation, we had proposed 9p21-22 and 16q22 as additional candidate loci. Whereas linkage to 9p21-22 can be excluded, the finding of a maximum two-point LOD score of 2.82 with the microsatellite marker D16S522 at a recombination fraction theta = 0 provides evidence supporting linkage to 16q22. Haplotype analysis reveals a 23.5-cM (17.9-Mb) commonly inherited region among all affected family members extending from D16S451 to D16S289. In order to extract maximum linkage information with missing individuals, incomplete informativeness with individual markers in this interval, and possible deviance from strict autosomal dominant inheritance, we performed nonparametric linkage analysis (NPL) and found a maximum NPL statistic corresponding to a P-value of .00098, close to the maximum conditional probability of linkage expected for a pedigree with this structure. Mutational analysis in this region specifically excludes expansion of the AT-rich minisatellite repeat FRA16B fragile site and the CAG trinucleotide repeat in the E2F-4 transcription factor. The "repeat expansion detection" method, capable of detecting dynamic mutation associated with anticipation, more generally excludes large CAG repeat expansion as a cause of leukemia in this family.

Tumor suppressor genes in normal and malignant hematopoiesis

“…When this disease progresses to AML, additional genetic changes occur which are not necessarily associated with the normal AML1 allele. Interestingly, another family with autosomal dominant inherited AML has been observed which was Tumor suppressor genes in hematopoiesis U Krug et al linked to an LOH at chromosome 16q22, the locus of CBFb (Horwitz et al, 1997). Possibly, haploinsuciency of CBFb might play a causative role in this syndrome.…”

No evidence for core-binding factor CBFβ as a leukemia predisposing factor in chromosome 16q22-linked familial AML

“…6 However, in two distinct pedigrees that showed autosomal dominant transmission of AML in three generations, linkage analysis excluded RUNX1 from being causative of the disease, but suggested a second locus for predisposition to leukemia on chromosome 16q22 between D16S451 and D16S515 where CBFb is located. 7,8 Owing to its close relationship to RUNX1 and its known involvement in leukemia as a translocation fusion partner, CBFb is an outstanding candidate gene for leukemia predisposition in these families. The CBFb gene has six exons and encodes a protein of 182 amino acids or 187 if an alternate splice donor site in exon 5 is used resulting in a different reading frame in exon 6.…”

In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis

“…2 Only 2 loci for familial hematologic malignancies have been identified to date, 1 on chromosome 21q22.1 3 and the other on 16q22. 4,5 These loci contain RUNX1 and PEBP2␤/CBF␤, respectively.Studies of families that demonstrate single-gene inheritance for leukemia predisposition should help to identify the genes and mechanisms involved in the first steps of leukemia development. The autosomal dominant familial platelet disorder (FPD)/ AML (acute myelogenous leukemia; Online Mendelian Inheritance in Man no.…”