Team 10 - Normal and leukemic hematopoietic stem cells.

Équipe 10 – Cellules souches hématopoïétiques normales et leucémiques.

Team N°10 of BRIC INSERM unit 1312 “Normal and Leukemic Hematopoietic Stem Cells: persistence, signaling and therapeutic targets” was born from the desire to establish ambitious research by bringing together several researchers, biologists and physicians to develop a fundamental and translational research on acute myeloblastic leukemia (AML). This team brings together the group of Dr Jean-Max Pasquet and Pr Arnaud PIGNEUX, head of the Department of Clinical Hematology and Cellular Therapy. The recent development of several targeted therapies in AML has greatly improved patient care and outcomes. All these improvements will not be able to continue without our progress in the knowledge of the leukemogenesis of AML.


Keywords

Acute Leukemia, Kinase, Inhibitors, Persistence, Resistance, Stem Cells

News


Projects

New oncogenic form of FLT3 receotor.

AML represent a heterogeneous group of hematological malignancies from a cytological, cytogenetic and molecular point of view. Splicing abnormalities have been described in AML contributing to their heterogeneity. Several studies show a deletion of one or more exons in many genes including FLT3, TET2 or NOTCH. Overall 30% of the genes expressed are abnormally spliced in these pathologies. This research axis focuses on the identification and characterization of new molecular abnormalities in AML, such as splicing abnormalities, in order to find novel therapeutic targets that could improve the treatment of patients with AML. The development of translational projects in collaboration with the Clinical Hematology Department of the Bordeaux University Hospital, will allow to determine whether the new variants identified may become molecular markers for prognosis and minimal residual disease.


Project members

Noteworthy publications
Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3-ITD Acute Myeloid Leukemia.
Dumas PY, Villacreces A, Guitart AV, El-Habhab A, Massara L, Mansier O, Bidet A, Martineau D, Fernandez S, Leguay T, Pigneux A, Vigon I, Pasquet JM, Desplat V
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2021 Nov 01
Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?
Fernandez S, Desplat V, Villacreces A, Guitart AV, Milpied N, Pigneux A, Vigon I, Pasquet JM, Dumas PY
International journal of molecular sciences ; 2019 Jul 12
Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.
Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, Pasquet JM
Haematologica ; 2019 Oct 01
Synthesis and Antiproliferative Effect of Ethyl 4-[4-(4-Substituted Piperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxalinecarboxylate Derivatives on Human Leukemia Cells.
Desplat V, Vincenzi M, Lucas R, Moreau S, Savrimoutou S, Rubio S, Pinaud N, Bigat D, Enriquez E, Marchivie M, Routier S, Sonnet P, Rossi F, Ronga L, Guillon J
ChemMedChem ; 2017 Jun 21
Synthesis and evaluation of the cytotoxic activity of novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives in myeloid and lymphoid leukemia cell lines.
Desplat V, Vincenzi M, Lucas R, Moreau S, Savrimoutou S, Pinaud N, Lesbordes J, Peyrilles E, Marchivie M, Routier S, Sonnet P, Rossi F, Ronga L, Guillon J
European journal of medicinal chemistry ; 2016 May 04

Hematopoietic Stem Cell fate regulation.

During development, HSCs emerge from the embryonic aorta and migrate to the fetal liver, a major hematopoietic site for their expansion and maturation. Fetal liver HSCs (FL-HSCs) are highly proliferative to ensure sustained production of functional blood cells, but also to generate the definitive pool of HSCs required to maintain adult hematopoiesis throughout life. Adult HSCs reside in the bone marrow (ABM-HSCs) and are predominantly quiescent (qHSCs), dividing only to maintain their numbers and generate multipotent (highly proliferative) progenitors. However, following stress, HSC proliferation is activated (aHSCs) in order to reconstitute the damaged blood system and/or to meet the needs of the immune system. Finally, over the years, the number of HSCs increases but their capacity for self-renewal decreases and their differentiation shifts towards the myeloid lineage; the incidence of hematological malignancies such as myeloproliferative disorders or myeloblastic leukemia increases with the appearance of leukemic stem cells (LSCs). In order to elucidate the mechanisms regulating the expansion/self-renewal (or even differentiation) of HSCs, we study HSCs in these different contexts HSC-FL, ABM-qHSC, ABM-aHSC and LSCs using mainly the mouse model (normal or transgenic).


Project members

Noteworthy publications
Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
Guitart AV, Panagopoulou TI, Villacreces A, Vukovic M, Sepulveda C, Allen L, Carter RN, van de Lagemaat LN, Morgan M, Giles P, Sas Z, Gonzalez MV, Lawson H, Paris J, Edwards-Hicks J, Schaak K, Subramani C, Gezer D, Armesilla-Diaz A, Wills J, Easterbrook A, Coman D, So CW, O'Carroll D, Vernimmen D, Rodrigues NP, Pollard PJ, Morton NM, Finch A, Kranc KR
The Journal of experimental medicine ; 2017 Mar 06
Ca2+tapulting HSCs into action.
Guitart AV, Finch AJ, Kranc KR
The Journal of experimental medicine ; 2018 Aug 06
Description of a knock-in mouse model of JAK2V617F MPN emerging from a minority of mutated hematopoietic stem cells.
Mansier O, Kilani B, Guitart AV, Guy A, Gourdou-Latyszenok V, Marty C, Parrens M, Plo I, Vainchenker W, James C
Blood ; 2019 Dec 26
α-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance.
Rodriguez L, Duchez P, Touya N, Debeissat C, Guitart AV, Pasquet JM, Vlaski-Lafarge M, Brunet de la Grange P, Ivanovic Z
Biomolecules ; 2021 Apr 10
CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.
Lawson H, van de Lagemaat LN, Barile M, Tavosanis A, Durko J, Villacreces A, Bellani A, Mapperley C, Georges E, Martins-Costa C, Sepulveda C, Allen L, Campos J, Campbell KJ, O'Carroll D, Göttgens B, Cory S, Rodrigues NP, Guitart AV, Kranc KR
Stem cell reports ; 2021 Nov 09

Resistance and persistence of acute myeloid leukemic stem cells.

Acute Myeloid Leukemias (AML) represent a heterogeneous group of aggressive hematological malignancies most often associated with poor prognosis. Their treatment still remains a major issue despite very encouraging results obtained with development of targeted therapies such as tyrosine kinase inhibitors (TKI) or inhibitors of the BCL2 and IDH1/2 proteins or novel combinations of chemotherapy. Although an improvement in patient survival is observed with these newest therapies, they do not allow the definitive elimination of AML initiating cells. Relapses related to various mechanisms are delayed but still persist.

Our objective is to characterize the mechanisms of resistance of AML cells to the most recent therapies within their microenvironment.  After providing proof of concept for the most promising candidate genes, we will evaluate their potential as new therapeutic targets or prognostic markers in collaboration with the clinical hematology department of the Bordeaux University Hospital.

 


Project members

Noteworthy publications
Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.
Dupont M, Huart M, Lauvinerie C, Bidet A, Guitart AV, Villacreces A, Vigon I, Desplat V, El Habhab A, Pigneux A, Ivanovic Z, Brunet De la Grange P, Dumas PY, Pasquet JM
Cancers ; 2022 Jan 17
Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3-ITD Acute Myeloid Leukemia.
Dumas PY, Villacreces A, Guitart AV, El-Habhab A, Massara L, Mansier O, Bidet A, Martineau D, Fernandez S, Leguay T, Pigneux A, Vigon I, Pasquet JM, Desplat V
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2021 Nov 01
Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?
Fernandez S, Desplat V, Villacreces A, Guitart AV, Milpied N, Pigneux A, Vigon I, Pasquet JM, Dumas PY
International journal of molecular sciences ; 2019 Jul 12
Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.
Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, Pasquet JM
Haematologica ; 2019 Oct 01
PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells.
Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E
Blood ; 2017 May 04

Jobs offers

postdoctoral position - team 10 - 01-2023
Published on 2023-01-24

Team: Team 10 - Normal and leukemic hematopoietic stem cells.

Chercheur contractuel / Researcher on contract • 2 + 1 year • Required education:

Teleworking acceptable

Expires on 2023-05-31

Read more »


Team’s noteworthy publications

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?
Fernandez S, Desplat V, Villacreces A, Guitart AV, Milpied N, Pigneux A, Vigon I, Pasquet JM, Dumas PY
International journal of molecular sciences ; 2019 Jul 12
Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.
Dupont M, Huart M, Lauvinerie C, Bidet A, Guitart AV, Villacreces A, Vigon I, Desplat V, El Habhab A, Pigneux A, Ivanovic Z, Brunet De la Grange P, Dumas PY, Pasquet JM
Cancers ; 2022 Jan 17
Protein Kinases in Leukemias.
De Sepulveda P, Pasquet JM
Cancers ; 2021 Jun 01
Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.
Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, Pasquet JM
Haematologica ; 2019 Oct 01
Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3-ITD Acute Myeloid Leukemia.
Dumas PY, Villacreces A, Guitart AV, El-Habhab A, Massara L, Mansier O, Bidet A, Martineau D, Fernandez S, Leguay T, Pigneux A, Vigon I, Pasquet JM, Desplat V
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2021 Nov 01


Partners

Team leaders

Jean-max PASQUET
Research Director / DR


Team members

Audrey BIDET
Clinician / PH

Laura DESBOURDES
Lecturer / MCU

Vanessa DESPLAT
Professor / PU

Pierre-Yves DUMAS
Professor Clinician / PU-PH

Ali EL HABHAB
Research and Teaching Assistant / ATER

Amélie GUITART
Researcher / CR

Claire LAUVINERIE
PhD Student / Doc

Nicolas LE CHEVALIER
Clinician / PH

Noel MILPIED
Professor Clinician Emeritus / PUPH-EM

Jean-max PASQUET
Research Director / DR

Arnaud PIGNEUX
Professor Clinician / PU-PH

Jean-Philippe VIAL
Clinician / PH

Isabelle VIGON
Researcher / CR

Arnaud VILLACRECES
Engineer / IE