title: Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies.
abstract: Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.
authors.affiliation: Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Minelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Maserati
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rossi
authors.forename: Maria Ester
authors.initials: ME
authors.lastname: Bernardo
authors.forename: Piero
authors.initials: P
authors.lastname: De Stefano
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Cecchini
authors.forename: Roberto
authors.initials: R
authors.lastname: Valli
authors.forename: Veronica
authors.initials: V
authors.lastname: Albano
authors.forename: Paolo
authors.initials: P
authors.lastname: Pierani
authors.forename: Anna
authors.initials: A
authors.lastname: Leszl
authors.forename: Laura
authors.initials: L
authors.lastname: Sainati
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo Curto
authors.forename: Cesare
authors.initials: C
authors.lastname: Danesino
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Pasquali
mesh_terms: D001791:Blood Platelet Disorders / Q000175:diagnosis / Q000235:genetics*; D001854:Bone Marrow Cells / Q000737:chemistry / Q000378:metabolism; D002648:Child; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D020732:Cytogenetic Analysis / Q000379:methods; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018740:Genetic Heterogeneity; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007558:Italy; D004915:Leukemia, Erythroblastic, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009006:Monosomy / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014314:Trisomy / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors