MultiOmic characteriZation of Acute Myeloid Leukemia Evolving From myelopRoliferative Neoplasm to Identify New Targeted Therapeutic Strategies

Sponsor
University Hospital, Angers
Study ID
NCT06022341
Status
Not Yet Recruiting

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Conditions

  • Myeloproliferative Neoplasm
  • Secondary Leukemia

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Multiomic characterization — OTHER
    Multiomics analysis include targeted-NGS with a 400-genes panel, RNA-seq and methylome. All the genomic libraries will be constructed at the genomic facility of Angers University Hospital and the sequencing will be performed on a NovaSeq6000 in the GenoBIRD Platform in Nantes. Bioinformatic analysis will be performed and will derive for each sample: SNV/Indel and CNV from DNA sequencing, expression of mRNA and lncRNA, genes fusion and splicing events from RNA-seq, and methylation beta-values from methylome.
  • In vitro drug screening — OTHER
    The drug screening will be performed on the 'NEXT-AML' platform at St-Louis Hospital, Paris. This platform uses a multiparametric screening strategy based on flow cytometry measurements of cell viability, cell differentiation and stem cell compartment. Primary patient cells will be cultured in a specific niche-like medium with amino-acids, cytokines and stromal cells (Dal Bello et al. 2022). Twenty-five drugs at 6 concentrations covering a 1000-fold concentration range will be studied for each sample.

Study Details

Myeloproliferative neoplasms (MPN) are chronic myeloid malignancies characterized by a risk of evolution to acute myeloid leukemia (AML). This unpredictable complication is associated with a grim outcome with median overall survival ranging between 2 to 10 months. To date, even allogeneic transplantation fails to significantly improve the prognosis. Biological and molecular mechanisms driving leukemic transformation are complex, ill-defined, and heterogeneous between patients. The investigator hypothesize that deciphering the molecular heterogeneity of post-MPN AML may lead identifying efficient drugs targeting of the most relevant leukemogenic pathways. Our main objective is to identify new targeted therapeutic approaches in post-MPN AML through in-depth characterization of the dysregulated pathways. The investigator will first characterize in an already annotated cohort of 120 post-MPN AML homogeneous patients subgroups using comprehensive multiomic analyses. Dysregulated pathways will be identified in each subgroup using the omics data and single-cell RNA-sequencing will be performed in a subset of patients in each subgroup. A customised drug-panel will be derived from the dysregulated pathway for an ex vivo drug screening, which will use a flow-cytometry read-out enabling to identity drug effect on cells survival, differentiation, and stemness. The 3 most promising drugs will be validated in a preclinical in vivo model of patient's derived xenograft (PDX) and their impact on clonal architecture will be studied in primary cell cultures using single-cell DNA-sequencing. Overall, this proposal may provide a better understanding of MPN leukemic transformation mechanisms and provide a path for personalized therapies. Our findings may therefore pave the way to drugs development in post-MPN AML that would provide a rationale for implementation of early clinical trials in these dreadful diseases.

Key Dates

First listed
Sep 1, 2023
Start date
Oct 15, 2023
Status verified
Aug 2023
Primary completion
Dec 31, 2027
Completion
Dec 31, 2028

Study Design

Enrollment
120 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE

Arms

  • Other: Leukemic transformation of myeloproliferative neoplasms
    120 patients will be studied for : * Multiomic characterization * In vitro drug screening

Primary Outcome Measure

Ward's minimum variance criterion to minimize the intra-cluster variance [ Time Frame: 24 months ]

Central Contacts

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