Lina Benajiba, MD, PhD
Assistant Professor
INSERM Institute of Health and Medical Research
Research project
Identification of Niche-Driven Chemo-Protective Pathways in Acute Myeloid Leukemia
Summary
Acute myeloid leukemia (AML) is a cancer caused by the uncontrolled growth of abnormal cells called blasts. As a result of blasts invasion, the bone marrow cannot produce normal blood cells. Current chemotherapy-based treatments are unfortunately not sufficient to cure all patients, and the development of new therapies is key to improve overall survival. The occurrence of AML is the consequence of both genetic abnormalities of leukemia cells - the "seeds" - and changes in their bone marrow microenvironment - the "soil". Recent studies have shown that the "soil" plays a key role in the proliferation, survival and therapy resistance of leukemic cells. The main objective of our research project is to discover new therapeutic targets mediating the "soils’" protective role. Blocking the "seeds" and the "soil" simultaneously should allow the eradication of leukemia cells and ultimately improve patient survival. To experimentally reproduce as closely as possible the real conditions of leukemia cells development within their original environment, we use a mouse model of AML developed within a humanized bone marrow niche. An innovative high-throughput genetic screening method will allow the identification of new therapeutic targets involved in the "seed-soil" relationship, and the understanding of the mechanisms underlying these dependencies. Our research should therefore open the road for the development of new therapeutic avenues for patients suffering from this dismal disease.
Impact
Despite the significant progress made in understanding Acute Myeloid Leukemia (AML) pathogenesis over the last decades, chemotherapy resistance remains challenging for most patients. Developing new translational research strategies focused on the identification of druggable oncogenic targets is critical to pave the way for successful AML treatment. Drug resistance is a complex process that does not depend only on the genetic alterations occurring in the leukemic cells ("the seeds"), it also relies on the critical role of the bone marrow niche ("the soil") in sustaining AML and regulating drug resistance.
The Leukemia Research Foundation funding allowed the identification of novel seed and soil crosstalk pathways involved in AML chemotherapy resistance. Through the use of a powerful large scale screening approach, we discovered a novel therapeutic target which inhibition potentiates sensitizes leukemic cells to chemotherapy. We are currently validating the clinical relevance of this newly identified therapeutic strategy using highly relevant preclinical models mimicking leukemic development within patients bone marrow. This steps should shed light on biomarkers of response to our novel “seeds” and “soil” synergistic therapeutic regimen.
Overall, this LRF funded project provides a path toward the discovery and preclinical validation of a promising therapeutic strategy to impair relapse and improve AML patients outcome.

Leukemia Research Foundation grant
$100K awarded in 2022
Disease focus
Acute myeloid leukemia (AML)
Research focus
Cancer cell biology (microenvironment)