Back to Search
Start Over
Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation.
- Source :
-
Blood [Blood] 2005 Jun 15; Vol. 105 (12), pp. 4664-70. Date of Electronic Publication: 2005 Mar 01. - Publication Year :
- 2005
-
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.
- Subjects :
- Adolescent
Adult
Alleles
Amino Acid Motifs
Blood Platelets metabolism
Blotting, Western
Core Binding Factor Alpha 2 Subunit
DNA metabolism
DNA Primers chemistry
Electrophoresis, Polyacrylamide Gel
Exons
Family Health
Female
Flow Cytometry
Frameshift Mutation
Gene Expression Regulation
Genetic Predisposition to Disease
Germ-Line Mutation
Heterozygote
Humans
Immunoblotting
Male
Middle Aged
Models, Genetic
Pedigree
Phosphorylation
Promoter Regions, Genetic
Protein Binding
RNA, Messenger metabolism
Receptors, Thrombopoietin
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Thrombocytopenia genetics
Thrombopoietin metabolism
Tyrosine chemistry
Tyrosine metabolism
Blood Platelet Disorders genetics
Blood Platelet Disorders metabolism
DNA-Binding Proteins genetics
Leukemia, Myeloid, Acute genetics
Mutation
Proto-Oncogene Proteins biosynthesis
Proto-Oncogene Proteins genetics
Receptors, Cytokine biosynthesis
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 105
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15741216
- Full Text :
- https://doi.org/10.1182/blood-2005-01-0050