Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia

NCT06246006 | Unknown

• 1 other identifier: NIMAO/2023-1/SC01
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Myeloproliferative Disorder

Keywords

leukemia; neoplasm; polymorphism; thrombocythemia; Thrombopoietin receptor,

Outcome Measures

Primary Outcomes (3)

• Growth of cultured cells with site-directed mutagenesis of identified variants in the presence of thrombopoietin

  Thrombopoietin concentration curve

  Day 0

• Ability of cultured cells with site-directed mutagenesis of identified variants to activate the MPL - JAK2 pathway

  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

  Western blot of JAK2, STAT (3 and 5) AKT, ERK1 /2 proteins

  Day 0

Study Arms (1)

Patients with suspected MPN

Other: Gene sequencing

Interventions

Gene sequencing OTHER

Next generation sequencing of candidate genes (JAK2, cMPL, CALR, ASXL1 and NF-E2)

Patients with suspected MPN

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patient with suspected MPN screened at CHU Nîmes

You may qualify if:

• Patient with suspected MPN

You may not qualify if:

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

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nīmes: lead

Study Sites (1)

CHU de Nîmes

Nîmes, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples and bone marrow samples will be taken depending on the clinical management of the patient

MeSH Terms

Conditions

Myeloproliferative Disorders; Leukemia; Neoplasms; Thrombocytosis

Interventions

Base Sequence

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Histologic Type; Blood Platelet Disorders

Intervention Hierarchy (Ancestors)

Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Genetic Structures; Genetic Phenomena

Study Officials

• Serge Carillo

  CHU de Nimes

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2024
• First Posted: February 7, 2024
• Study Start: October 1, 2023
• Primary Completion: April 1, 2025
• Study Completion: April 1, 2025
• Last Updated: February 7, 2024

Record last verified: 2024-01

Locations

FR (1)