Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia (MPL - NPM)
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
-
-
-
Nîmes, France
- Chu de Nimes
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
• Patient with suspected MPN
Exclusion Criteria:
• Patient with variant of cMPL already described in the literature.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
|---|---|
|
Patients with suspected MPN
|
Next generation sequencing of candidate genes (JAK2, cMPL, CALR, ASXL1 and NF-E2)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Growth of cultured cells with site-directed mutagenesis of identified variants in the presence of thrombopoietin
Time Frame: Day 0
|
Thrombopoietin concentration curve
|
Day 0
|
|
Ability of cultured cells with site-directed mutagenesis of identified variants to activate the MPL - JAK2 pathway
Time Frame: Day 0
|
STAT5 Luciferase reporter system
|
Day 0
|
|
Ability of cultured cells with site-directed mutagenesis of identified variants to phosphorylate proteins in the MPL - JAK2 pathway
Time Frame: Day 0
|
Western blot of JAK2, STAT (3 and 5) AKT, ERK1 /2 proteins
|
Day 0
|
Collaborators and Investigators
Investigators
- Principal Investigator: Serge Carillo, Chu de Nimes
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NIMAO/2023-1/SC01
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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