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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Patients with a prior diagnosis of MPN: polycythemia vera, essential thrombocythemia or primary myelofibrosis according to the WHO criteria
* Acute myeloid leukemia evolution defined by ≥ 20% of blasts cells
* Available material from bone marrow sampling at the time of leukemic transformation (i.e. ≥ 20% of blasts cells): DNA (1µg), RNA (500ng) +/- frozen mononuclear cells in DMSO for a subset of 60 patients (2 vials of at least 8 millions cells).
* Informed consent (or requalification procedure)

Exclusion Criteria:

\- Patient not affiliated to the French health insurance