^-A ⁺A

UMR 1131 – Equipe 3 - Cellules souches et voies de signalisation

UFR de rattachement >

Institut Universitaire d'Hématologie

Présentation

Group Acute transformation and epigenetics:

Epigenetic and transcription alterations play a crucial role in the development and maintenance of acute myeloid leukemias. Recurrent somatic mutations in genes encoding epigenetic regulators (e.g. TET2, ASXL1, EZH2 or DNMT3A) have been detected in myeloid malignancies such as acute myeloid leukemias (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), especially during their progression to leukemia. Importantly, some of these somatic mutations can also be detected in clonal hematopoietic expansions of healthy subjects, events associated with increased risks of hematologic cancer, suggesting that these mutations could contribute to the initiation of myeloid malignancies. Reciprocal translocations such as t(15;17); t(11;17) or t(18;21) studied in the past by the team, produce altered transcription factors that strongly interact with co-repressors (including DNMTs and HDCAs). The team has shown that reversal of malignancies by differentiating agents (ATRA; G-CSF, CD44 activating Mab or GSK3 inhibitors) is mediated in part by restoration of promoter permissiveness (Cras 2012,Cassinat 2011, Zassadowski 2014) and allows to prolong survival in mouse models or xenografts while targeting leukemia initiating stem cells. The team has recently established that PLZF, an epigenetic repressor, whose activity is altered in myeloid malignancies and which is essential for germ cells and hematopoietic stem cells maintenance, also contributes to LINE-1 retrotransposon silencing (Puszyk 2013).

The team is now focusing on:

establishing the role of epigenetic regulation in the protection of stem cells to environmental stress
describing the dysregulation of epigenetic regulation in the transformation of chronic myeloid malignancies such as MPNs and MDS
describing the differential gene expression triggered by differentiating drugs and epigenetic agents on epigenetic regulators and stem cell genes

Key findings:

Efficacy of ATRA in APL and Solid Tumors
Role of chromatin modifications in resistance to differentiating agents
Differentiating efficacy of CD44 activation on AML and targeting of LICs
LICs in AML3
Control of LINE-1 retrotransposon expression and mobility by PLZF

Equipes de recherche

Pr Christine Chomienne MD, PhD

Fabien Guidez PhD

Laetitia Durand INSERM Technical assistant

Lise Coste-Sarguet Technical assistant

Masters students

Publications

CAYE A, STRULLU M, GUIDEZ F, CASSINAT B, GAZAL S, FENNETEAU O, LAINEY E, NOURI K, NAKHAEI-RAD S, DVORSKY R, LACHENAUD J, PEREIRA S, VIVENT J, VERGER E, VIDAUD D, GALAMBRUN C, PICARD C, PETIT A, CONTET A, POIREE M, SIRVENT N, MECHINAUD F, ADJAOUD D, PAILLARD C, NELKEN B, REGUERRE Y, BERTRAND Y, HÄUSSINGER D, DALLE JH, AHMADIAN MR, BARUCHEL A, CHOMIENNE C, CAVE H.

Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.

Nat Genet. 2015 Nov;47

PROST S, RELOUZAT F, SPENTCHIAN M, OUZEGDOUH Y, SALIBA J, MASSONNET G, BERESSI JP, VERHOEYEN E, RAGGUENEAU V, MANEGLIER B, CASTAIGNE S, CHOMIENNE C, CHRETIEN S, ROUSSELOT P, LEBOULCH P.

Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.

Nature. 2015 Sep 17;525(7569):380-3

MCCONNELL MJ, DURAND L, LANGLEY E, COSTE-SARGUET L, ZELENT A, CHOMIENNE C, KOUZARIDES T, LICHT JD, GUIDEZ F.

Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases.

Epigenetics Chromatin. 2015 Sep 24;8:38

ZASSADOWSKI F, POKORNA K, FERRÉ N, GUIDEZ F, LLOPIS L, CHOURBAGI O, CHOPIN M, POUPON J, FENAUX P, PADUA RA, PLA M, CHOMIENNE C, Cassinat B, Lithium choride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent . Leukemia 2015 Dec;29(12):2277-84

DUVAL R, FRITSCH L, BUI LC, BERTHELET J, GUIDEZ F, MATHIEU C, DUPRET JM, CHOMIENNE C, AIT-SI-ALI S AND RODRIGUES-LIMA F. An acetyltransferase assay for CREBP-binding protein based on reverse phase-ultra-fast chromatography of fluorescent histone H3 peptides Anal Biochem. 2015 1;486:35-7.

PUSZYK W, DOWN T, GRIMWADE D, CHOMIENNE C, OAKEY RJ, SOLOMON E, GUIDEZ F The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells.

Embo J. 2013 Jul 3;32(13):1941-52.

VALENT P, BONNET D, WÖHRER S, ANDREEFF M, COPLAND M, CHOMIENNE C, EAVES C.

Heterogeneity of neoplastic stem cells: theoretical, functional, and clinical implications.

Cancer Res. 2013 Feb 1;73(3):1037-45.

VALENT P, BONNET D, DE MARIA R, LAPIDOT T, COPLAND M, MELO JV, CHOMIENNE C, ISHIKAWA F, SCHURINGA JJ, STASSI G, HUNTLY B, HERRMANN H, SOULIER J, ROESCH A, SCHUURHUIS GJ, WÖHRER S, AROCK M, ZUBER J, CERNY-REITERER S, JOHNSEN HE, ANDREEFF M, EAVES C

Cancer stem cell definitions and terminology: the devil is in the details..

Nat Rev Cancer. 2012 Nov;12(11):767-75

PATEL S, ZHANG Y, CASSINAT B, ZASSADOWSKI F, FERRE N, CUCCUINI W, CAYUELA JM, FENAUX P, BONNET D, CHOMIENNE C*, LOUACHE F*. Successful xenografts of AML3 samples in immune deficient NOD/shi-SCID IL2Rγ (-/-) mice. * co-senior authors

Leukemia 2012 Nov;26(11):2432-5.

Cras A, Politis B, Balitrand N, Darsin-Bettinger D, Boelle PY, Cassinat B, Toubert ME, Chomienne C. Bexarotene via CBP/p300 induces suppression of NF-kappaB-dependent cell growth and invasion in thyroid cancer.

Clin Cancer Res. 2012 Jan 15;18(2):442-5

Cassinat B, Zassadowski F, Ferry N, Llopis L, Bruck N, Lainey E, Duong V, Cras A, Despouy G, Chourbagi O, Beinse G, Fenaux P, Rochette Egly C, Chomienne C.

New Role for G-CSF-induced Extracellular signal-Regulated Kinase1/2 in histone modification and Retinoic Acid Receptor {alpha} recruitment to gene promoters: relevance to Acute Promyelocytic Leukemia cell differentiation.

Mol Cell Biol. 2011 Apr;31(7):1409-18.

Autres contacts

Chefs d'équipes :

Pr. Christine Chomienne MD, PhD, HDR

University Paris-Diderot (Paris-Sorbonne-Cité)

INSERM UMR-S1131 – Institut Universitaire d’Hématologie

Hôpital Saint-Louis (AP-HP)

Tél. : +33 1 57 27 90 10

FAX : +33 1 57 27 90 11

Email: christine.chomienne@aphp.fr

Fabien Guidez, PhD, HDR