Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia

Myeloproliferative Disorder Clinical Trial

— MPL - NPM  

Official title:

Functional Characterization of Thrombopoietin/cMPL Receptor Mutations in Myeloproliferative Neoplasia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06246006
• Other study ID #: NIMAO/2023-1/SC01
• Status: Active, not recruiting
• Start date: October 1, 2023
• Est. completion date: April 2025

Study information

• Verified date: January 2024
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Patient with suspected MPN

Exclusion Criteria:

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

Related Conditions & MeSH terms

• Myeloproliferative Disorder
• Myeloproliferative Disorders

Intervention

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

Locations

Country	Name	City	State
France	CHU de Nîmes	Nîmes

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Growth of cultured cells with site-directed mutagenesis of identified variants in the presence of thrombopoietin	Thrombopoietin concentration curve	Day 0
Primary	Ability of cultured cells with site-directed mutagenesis of identified variants to activate the MPL - JAK2 pathway	STAT5 Luciferase reporter system	Day 0
Primary	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