Project 4 : Bone marrow supportive niches in B-ALL

Research Topic

Stéphane Mancini, PhD, HDR (Inserm researcher, PI); Tony Marchand, MD PhD (hematologist, PI); Jérôme Destin (engineer); Mourad Ounis (PhD student)

We and others have identified different niches controlling early hematopoiesis and B lymphopoiesis in the bone marrow (BM) (Aurrand-Lions and Mancini, IJMS 2018). We identified the molecular interactions allowing the specific retention of pro-B cell in their IL7+ supportive niche and found that they are conserved between mouse and human (Balzano et al., Cell Reports 2019). Furthermore, we found that Galectin-1 (GAL1) is a ligand for the pre-BCR and is involved in the control of proliferation and differentiation of pre-B cells towards the BCR+ immature B cell stage (Espeli*, Mancini* et al., Blood 2009). Most importantly, pre-B/GAL1+ stromal cell interactions required for pre-BCR signalling amplification could be visualized in the BM (Mourcin et al., Blood 2011).

B-cell acute lymphoblastic leukemia (B-ALL), the malignant counterpart of BM differentiating B cells, represent the most common cancer in childhood and, although less frequent, correspond to a similar number of cases in adults. New combinations of chemotherapeutic agents, have dramatically improved disease outcome in young patients, but the overall survival of adults at diagnosis and after relapse for all the patients remains low. Resistance to treatment in B-ALL relies on protective cues provided by BM stromal cells (Delahaye et al., Front Oncol 2021). Our recent results demonstrate that Galectin-1 is not only implicated in the proliferation of normal pre-B cells, but also of their leukemic counterparts indicating that similar extrinsic cues drive normal and pathological B cell development.

Specific aims addressed in our project

Using human samples and mouse models, our aim is to understand the molecular mechanisms allowing the adaptation of the supportive BM microenvironment to pathological B cell development and to identify druggable targets involved in resistance to treatment.

PUBLICATIONS

Link to PubMed

Balzano M, De Grandis M, Vu Manh T-P, Chasson L, Bardin F, Farina A, Sergé A, Bidaut G, Charbord P, Hérault L, Bailly A-L, Cartier-Michaud A, Boned A, Dalod M, Duprez E, Genever P, Coles P, Bajenoff M, Xerri L, Aurrand-Lions M, Schiff C, Mancini SJ.

Nidogen-1 contributes to the interaction network involved in pro-B cell retention in the peri-sinusoidal hematopoietic stem cell niche.

Cell Reports. 2019. 26(12):3257-3271.

In the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are the main source of IL-7, but their characterization as a pro-B cell niche remains limited. Here, we characterize pro-B cell supporting stromal cells and decipher the interaction network allowing pro-B cell retention. Preferential contacts are found between pro-B cells and PSS cells, which homogeneously express HSC and B cell niche genes. Furthermore, pro-B cells are frequently located in the vicinity of HSCs in the same niche. Using an interactome bioinformatics pipeline, we identify Nidogen-1 as essential for pro-B cell retention in the peri-sinusoidal niche as confirmed in Nidogen-1−/− mice. Finally, human pro-B cells and hematopoietic progenitors are observed close to similar IL-7+ stromal cells. Thus, a multispecific niche exists in mouse and human supporting both early progenitors and committed hematopoietic lineages.

Pinho S, Marchand T, Yang E, Wei Q, Nerlov C, Frenette PS

Lineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches

Developmental Cell. 2018. 44(5):634-641.

The spatial localization of hematopoietic stem cells (HSCs) in the bone marrow (BM) remains controversial, with some studies suggesting that they are maintained in homogeneously distributed niches while others have suggested the contributions of distinct niche structures. Subsets of quiescent HSCs have been reported to associate with megakaryocytes (MK) or arterioles in the BM. However, these HSC subsets have not been prospectively defined. Here, we show that platelet and myeloid-biased HSCs, marked by von Willebrand factor (vWF) expression, are highly enriched in MK niches. Depletion of MK selectively expands vWF+ HSCs, whereas the depletion of NG2+ arteriolar niche cells selectively depletes vWF- lymphoid-biased HSCs. In addition, MK depletion compromises vWF+ HSC function by reducing their long-term self-renewal capacity and eliminating their lineage bias after transplantation. These studies demonstrate the existence of two spatially and functionally separate BM niches for HSC subsets with distinct developmental potential.

We are looking for a highly dynamic, flexible and proactive post doc to start in our team as soon as possible.

All the details in the following link: