Myeloproliferative Disorder
Conditions
Keywords
leukemia, neoplasm, polymorphism, thrombocythemia, Thrombopoietin receptor,
Brief summary
The MPL gene is implicated in two groups of hematological pathologies: congenital amegakaryocytic thrombocytopenia (CAMT) and Phi negative myeloproliferative neoplasia (MPN). Fifty germline mutations have been identified in CAMT, yet only a dozen activating mutations have been described in MPN. Most are somatic, distributed mainly in the transmembrane (TM) and juxtamembrane (JM) domains. However, a few rare germline mutations located in the extracellular domain (ECD) have also been reported: K39N, R102P and P106L. Next generation sequencing technology has been used to study the complete MPL gene, identifying numerous variants, most of unknown significance. The study investigators have a series comprising 41 variants of unknown significance, whose allelic frequencies suggest a germline origin for 80% of them. Their distribution within the MPL gene is similar to that of inactivating mutations, except that they were discovered in the context of suspected myeloproliferative disease. Characterizing the activity of these variants would confirm the diagnosis of MPN, opening the door to specific treatment (cytoreductive, JAK2 inhibitor or interferon). It also has an important prognostic value, particularly in the case of MPN, for which life expectancy varies from 5 to 7 years, with terminal progression to acute myeloid leukemia (AML in 15 to 20% of cases) or bone marrow failure. Using a battery of functional assays, this study aims to characterize these variants.
Interventions
OTHERGene sequencing
Next generation sequencing of candidate genes (JAK2, cMPL, CALR, ASXL1 and NF-E2)
Sponsors
Centre Hospitalier Universitaire de Nīmes
Study design
Observational model
CASE_ONLY
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
• Patient with suspected MPN
Exclusion criteria
• Patient with variant of cMPL already described in the literature.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Growth of cultured cells with site-directed mutagenesis of identified variants in the presence of thrombopoietin | Day 0 | Thrombopoietin concentration curve |
| Ability of cultured cells with site-directed mutagenesis of identified variants to activate the MPL - JAK2 pathway | Day 0 | STAT5 Luciferase reporter system |
| Ability of cultured cells with site-directed mutagenesis of identified variants to phosphorylate proteins in the MPL - JAK2 pathway | Day 0 | Western blot of JAK2, STAT (3 and 5) AKT, ERK1 /2 proteins |
Countries
France
Outcome results
None listed