Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia (MPL - NPM)

January 30, 2024 updated by: Centre Hospitalier Universitaire de Nīmes

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

Active, not recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Actual)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Nîmes, France
        • Chu de Nimes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patient with suspected MPN screened at CHU Nîmes

Description

Inclusion Criteria:

• Patient with suspected MPN

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Patients with suspected MPN
Other: Gene sequencing
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

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire de Nīmes

Investigators

  • Principal Investigator: Serge Carillo, Chu de Nimes

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2023

Primary Completion (Estimated)

April 1, 2025

Study Completion (Estimated)

April 1, 2025

Study Registration Dates

First Submitted

January 30, 2024

First Submitted That Met QC Criteria

January 30, 2024

First Posted (Actual)

February 7, 2024

Study Record Updates

Last Update Posted (Actual)

February 7, 2024

Last Update Submitted That Met QC Criteria

January 30, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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