Background:Characterization of hematopoietic stem cell (HSC) properties and understanding the mechanisms controlling their status in physiological and pathological settings are major challenges in oncohematology. HSCs are first generated from hemogenic endothelial cells during a short window of time of embryogenesis, transit through different anatomical niches before colonizing the bone marrow, which is the main hematopoietic organ in adults. The surrounding microenvironments of HSCs provide essential cues that direct their cell fate decisions. Our work is dedicated to the identification of new players controlling the emergence and homeostasis of HSCs. Indeed, our work has shown that ASB2α (Ankyrin repeat-containing protein with a Suppressor of cytokine signalling Box 2 alpha) is the specificity subunit of an E3 ubiquitin ligase complex suggesting that ASB2α exerts its effects in hematopoiesis through the targeting of specific substrates for degradation by the proteasome. Two ASB2α substrates have been described so far in hematopoietic cells: (i) filamins that are mediators of actin cytoskeleton reorganization and regulators of integrin-dependent cell motility and (ii) the Mixed Lineage Leukemia protein, an activator of Hox genes and a regulator of HSC self-renewal and hematopoietic progenitor proliferation. Because these proteins are regulators of cell fate and motility of hematopoietic precursors, two important biological events in HSC biology, it is tempting to speculate that by targeting its substrates to degradation, ASB2α may modulate the status of HSCs. We are using state-of-the-art mouse mutant models to perform cellular and molecular analyses in order to investigate the role of ASB2α in HSCs and the impact of its deregulation /dysfunction in hematopoietic neoplasm development.

Relevant publications:

1- Zakaria R, Lamsoul I, Uttenweiler-Joseph S, Erard M, Monsarrat B, Burlet-Schiltz O, Moog-Lutz C, Lutz PG. Phosphorylation of serine 323 of ASB2α is pivotal for the targeting of filamin A to degradation. Cell Signal. 2013 Dec;25(12):2823-30.
2- Lamsoul I, Métais A, Gouot E, Heuzé ML, Lennon-Duménil AM, Moog-Lutz C, Lutz PG. ASB2α regulates migration of immature dendritic cells.Blood. 2013 Jul 25;122(4):533-41.
3- Lamsoul I, Erard M, van der Ven PF, Lutz PG. Filamins but not Janus kinases are substrates of the ASB2α cullin-ring E3 ubiquitin ligase in hematopoietic cells.PLoS One. 2012;7(8):e43798.
4- Lamsoul I, Burande CF, Razinia Z, Houles TC, Menoret D, Baldassarre M, Erard M, Moog-Lutz C, Calderwood DA, Lutz PG. Functional and structural insights into ASB2alpha, a novel regulator of integrin-dependent adhesion of hematopoietic cells. J Biol Chem. 2011 Sep 2;286(35):30571-81.

Invitation: Laurent Delva- UMR866

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