Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia

Active, not recruiting

• Conditions: Myeloproliferative Disorder
• Interventions: Other: Gene sequencing

• Registration Number: NCT06246006
• Lead Sponsor: Centre Hospitalier Universitaire de Nīmes

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-10-01
• Status Verified: 2024-01
• Study First Submitted: 2024-01-30
• Study First Submitted QC: 2024-01-30
• Last Update Submitted: 2024-01-30
• Study First Posted: 2024-02-07
• Last Update Posted: 2024-02-07
• Primary Completion: 2025-04
• Study Completion: 2025-04

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Patient with suspected MPN

Exclusion Criteria

• Patient with variant of cMPL already described in the literature.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients with suspected MPN	Gene sequencing	-

Primary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

CHU de Nîmes; 🇫🇷 Nîmes, France