Fundamental to Translational Research on Dysregulated Hematopoiesis

Cancer cells reprogram their metabolic pathways to optimize nutrient and energy supplies for exacerbated proliferation, escape from apoptosis, and resistance to treatment. Targeting their deregulated metabolism could lead to new antitumor strategies.

The bone marrow microenvironment (BMME) is a complex ecosystem that instructs and protects hematopoietic stem cells (HSCs) and their malignant counterparts, leukemia stem cells/leukemia initiating cells (LSCs/ICs). Among the different functional exchanges that take place in the BMME, organelle transfer is now recognized as an important mode of intercellular communication, along with the role of adhesion molecules, secreted cytokines, and (onco)metabolites.

Using a coculture model mimicking the hematopoietic niche, we demonstrated that Acute Myeloid Leukemia (AML) cells subjected to chemotherapeutic stress trigger a unidirectional transfer of active mitochondria from surrounding bone marrow stromal cells. This uptake of mitochondria increases their mass and mitochondrial fitness, enhances their long-term leukemic culture initiation potential and their resistance to chemotherapy.

Targeting the mitochondrial transfer that provides a clear survival advantage to leukemic cells could represent an additional new strategy to interfere with the supportive actions of the BMME during leukemia progression and relapse.

Based on the knowledge of high-resolution atomic interactions of the protein synthesis inhibitor cycloheximide (CHX) with the human 80S ribosome, we created a consortium in 2017 consisting of three teams: Bruno Klaholz's biochemistry laboratory (IGBMC, Illkirch) for cryo-EM structures, Jean-Yves Winum's laboratory (Institut des Biomolécules Max Mousseron, Montpellier) for organic and medicinal chemistry, and J-F Peyron's laboratory (C3M, Nice) for in vitro and in vivo functional characterization of anticancer molecules. We have developed a drug-design strategy using the knowledge of the CHX-80S structure to synthesize more efficient and selective CHX derivatives with antileukemic properties. These new derivatives are currently being characterized in vitro: analysis of antileukemic effects against human and murine L/LAL-T lines and toxicity against healthy cells. A selection of the most effective and least toxic molecules will be tested in a LAL-T-PDX (Patient-derived Tumor Xenografts) model.

This project is supported by InCa (PLBIO 2016 and 2021).

In a core program, we developed a strategy to act "downstream" of the polycomb protein Bmi1, crucial for the self-renewal function of normal or cancerous stem cells, by a bioinformatics approach using the Connectivity Map (cmap) database. This allowed us to identify molecules belonging to the bis-biguanide family, some of which were found to have a strong antitumor potential in Chronic Myeloid Leukemia CML cell lines.  More interestingly, these bis-biguanides potentiate the effects of BCR-ABL inhibitors (ITKs) on both sensitive and resistant cells.

In a second core program, we have shown the involvement of PKC delta in the signaling pathway between BCR-ABL and the regulation of Bmi1 gene expression. In a collaboration with an American team specialized in the synthesis of kinase inhibitors, we used a specific inhibitor of PKCd (BJE6) and showed its ability to potentiate the effect of TKIs and target the leukemic stem cell compartment in stromal cell coculture systems.

This project was funded by FiLMC-Pfizer and Cancéropôle PACA.

NF-kappaB is a transcription factor that controls multiple cellular processes essential for immunity, inflammation, tumor development, chemoresistance and radioresistance. Our team has contributed significantly to the identification of this protumor role of NF-kappaB.

We have an in vivo model representative of human T-cell Lymphoma and Acute Lymphoblastic Leukemia (LL-T/LAL-T), generated by deletion of the tumor suppressor gene PTEN specifically in T cells (tPTEN-/-). The absence of PTEN leads to abnormal constitutive activation of the PI3K-Akt-mTOR axis, a feature found with high frequency in human pathology. During the characterization of  the deregulated signaling pathways in this tPTEN-/- model, we observed a constitutive activation of NF-kappaB. To better understand its role in lymphoma initiation and progression, we adopted a genetic approach. Thus, the invalidation of NF-kappaB in the tPTEN-/- model allowed us to observe a tumor suppressor role for NF-kappaB in lymphoma. We are currently studying this role at different levels: antitumor response, gene stability.

This project is supported by the ARC Foundation.