title: Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation.
abstract: Germ-line heterozygous mutations in the hematopoietic transcription factor AML1 (RUNX1) have been identified in patients with familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML), which is characterized by thrombocytopenia, abnormal platelet function, and propensity to myeloid malignancies. We identified a novel mutation in the AML1 gene in an FPD/AML pedigree characterized by a single nucleotide deletion that generates a frameshift and premature chain termination (Pro218fs-Ter225). Both wild-type and mutant transcripts were expressed in affected individuals by allele-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Thrombopoietin (TPO) binds to the Mpl receptor and is the major regulator of megakaryopoiesis. To explore the mechanisms underlying thrombocytopenia, we studied the TPO/Mpl pathway in this newly identified pedigree. TPO levels were mildly to moderately elevated. On flow cytometry and immunoblotting, Mpl receptor expression was decreased and TPO-induced signaling was impaired. While no mutations were identified in the MPL gene by sequence analysis, low MPL mRNA levels were found, suggesting decreased gene expression. Of particular interest, several AML1-binding motifs are present in the MPL promoter, suggesting MPL is an AML1 target. In conclusion, we identified a C-terminal AML1 mutation that leads to a decrease in Mpl receptor expression, providing a potential explanation for thrombocytopenia in this FPD/AML pedigree.
authors.affiliation: Division of Hematology, Instituto de Investigaciones Médicas Alfredo Lanari, University of Buenos Aires, Argentina. idimhematologia@hotmail.com <idimhematologia@hotmail.com>
authors.forename: Paula G
authors.initials: PG
authors.lastname: Heller
authors.forename: Ana C
authors.initials: AC
authors.lastname: Glembotsky
authors.forename: Manish J
authors.initials: MJ
authors.lastname: Gandhi
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Cummings
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Pirola
authors.forename: Rosana F
authors.initials: RF
authors.lastname: Marta
authors.forename: Laura I
authors.initials: LI
authors.lastname: Kornblihtt
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Drachman
authors.forename: Felisa C
authors.initials: FC
authors.lastname: Molinas
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D020816:Amino Acid Motifs; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D050676:Core Binding Factor Alpha 2 Subunit; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005192:Family Health; D005260:Female; D005434:Flow Cytometry; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000096:biosynthesis*; D053628:Receptors, Thrombopoietin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000235:genetics; D013926:Thrombopoietin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C493728:RUNX1 protein, human; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D014157:Transcription Factors; C082218:MPL protein, human; D014443:Tyrosine; D004247:DNA; D013926:Thrombopoietin