Tarik Möröy, IRCM, Major discoveries in career 1986-2020

Role of GFI1B in blood coagulation 

Beauchemin H, Shooshtarizadeh P, Pinder J, Dellaire G and Möröy T.
Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice.
Haematologica, 2020, Oct 1;105(10):2457-2470. doi: 10.3324/haematol.2019.222596.

Link between Gfi1b and beta-catenin/Wnt signaling

Shooshtarizadeh P, Helness A, Vadnais C, Brouwer N, Beauchemin H, Chen R, Bagci H, Staal FJT, Coté FJ and Möröy T.
Gfi1b regulates the level of Wnt/β-catenin signaling in hematopoietic stem cells and megakaryocytes
Nat. Commun., 2019, 20;10(1):1270.

New role for Gfi1 in DNA repair

Vadnais C, Chen R, Fraszczak J, Yu Z, Boulais J, Pinder J, Frank D, Khandanpour C, Hébert J, Dellaire G, Côté JF, Richard S, Orthwein A, Drobetsky E, Möröy T.
GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1.
Nat Commun. 2018 Apr 12;9(1):1418.

Gfi1b controls platelet production by regulating integrin signaling

Beauchemin H, Shooshtarizadeh P, Vadnais C, Vassen L, Pastore YD, Möröy T.
Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes.
Haematologica. 2017 Mar;102(3):484-497.

The RNA binding protein and splice factor hnRNP L has a role in hematopoietic stem cells

Gaudreau MC, Grapton D, Helness A, Vadnais C, Fraszczak J, Shooshtarizadeh P, Wilhelm B, Robert F, Heyd F, Möröy T.
Heterogeneous Nuclear Ribonucleoprotein L is required for the survival and functional integrity of murine hematopoietic stem cells.
Sci. Reports, 2016, June 7; 6: 27379

A genetic variant of GFI1 affects MDS to AML progression (co-discovery with Cyrus Khandanpour, a previous Möröy lab member)

Hönes JM, Botezatu L, Helness A, Vadnais C, Vassen L, Robert F, Hergenhan SM, A, Schütte J, Al-Matary YS, Lams RF, Fraszscak J, Makishima H, Radivoyevitch T, Przychodzen B, da Conceição Castro SV, Görgens A, Giebel B, Klein-Hitpass L, Lennartz K, Heuser M, Thiede C, Ehninger G, Dührsen U, Maciejewski J, Möröy T*, Khandanpour C*. (co-senior author)
GFI1 as a novel prognostic and therapeutic factor for AML/MDS
Leukemia. 2016, June 30(6): 1237-45.

A new mechanism to keep the p53 guardian of the genome in check during V(D)J recombination

Rashkovan M, Vadnais C, Ross J, Gigoux M, Suh WK, Gu W and Möröy T.
Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination.
Proc. Natl. Acad. Scie. (USA), 2014, Dec 16;111(50):E5411-9.

First description that alternative splicing creates a new “circadian clock gene” (co-discovery with Florian Heyd, a previous Möröy lab member)

Preußner M, Wilhelmi I, Schultz AS, Finkernagel F, Michel M, Möröy T, Heyd F.
Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian
clock in mice.
Mol Cell. 2014 May 22;54(4):651-62.

Gfi1 as a regulator of the p53 tumor suppressor and gatekeeper protein in lymphoid leukemia

Khandanpour C, Phelan JD, Vassen L, Schütte J, Chen R, Horman S, Gaudreau MC, Krongold J, Zhu J, Paul WE, Dührsen U, Göttgens B, Grimes HL and Möröy T.
Growth factor independence 1 (Gfi1) antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia.
Cancer Cell, 2013, Feb 11;23:200-214.

Khandanpour C and Möröy T.
Gfi1 as a regulator of p53 and a therapeutic target for ALL.
Oncotarget, 2013, Mar;4(3):374-5.

Discovery of a variant allele of Gfi1 associated with human AML and Myelodisplastic Syndrome

Khandanpour C,Thiede C, Valk, PJM, Sharif-Askari E, Nückel H, Lohmann D, Horsthemke B, Siffert W, Neubauer A, Grzeschik KH, Bloomfield CD, Marcucci G, Maharry K, Slovak ML, van der Reijden BA, Jansen JA, Schackert HK, Afshar K, Schnittger S, Peeters JK, Kroschinsky F, Ehninger G, Lowenberg B, Dührsen D and Möröy T
A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia
Blood, 2010, Mar 25;115(12):2462-72.

Khandanpour C, Krongold J, Schütte J, Bouwman F, Vassen L, Chen R, Gaudreau MC, Van der Reijden B, Hannah R, Diamanti E, Nieto FC, Meyer S, Grimes HL, Jansen J, Lowenberg B, Peeters JK, Patel C, Duehrsen U, Göttgens B, and Möröy T.
The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice
Blood, 2012, Nov 8;120(19):4006-17.

First conditional knockout of Gfi1b and description of its activity in controlling the expansion of hematopoietic stem cells

Khandanpour C, Sharif-Askari E, Gaudreau MC, Vassen L, Zhu J, Paul W, Okoyama T, Kosan C, and Möröy T.
Evidence that Growth factor independence 1b (Gfi1b) regulates dormancy and peripheral blood of hematopoietic stem cells
Blood, 2010, Dec 9;116(24):5149-61. (Faculty 1000 Rating 6)

Discovery of a new immune cell regulator: the POZ/BTB domain protein Miz-1

Kosan C, Saba I, Godmann M, Herold S, Herkert B, Eilers M and Möröy T.
The BTB/POZ domain protein Miz-1 (Zbtb17) is required to regulate IL-7 receptor signaling at early commitment stages of B cell differentiation.
Immunity, 2010, Dec 14;33(6):917-28.

Saba, I, Kosan C and Möröy T.
IL-7R-dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1.
Blood, 2011 Mar 24;117(12):3370-81.

Saba, I, Kosan C, Vassen L, Klein-Hitpass L and Möröy T.
Miz-1 is required to coordinate the expression of TCRbeta and p53 effector genes at the pre-TCR “beta-selection” checkpoint
Journal of Immunology, 2011, Sep 15;187(6):2982-92.

Alternative splicing as a mechanisms to control the activity of T-cells

Gaudreau MC, Heyd F, Bastien R, Wilhelm B and Möröy T.
Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L (hnRNP L) regulates development, proliferation and migration of thymic pre-T cells
J. Immunol., 2012, Jun 1;188(11):5377-88.

Heyd F, ten Dam G and Möröy T.
Auxiliary splice factor U2AF26 and the transcription factor Gfi1 directly cooperate in the regulation of CD45 alternative splicing.
Nature Immunology, 2006, Aug;7(8):859-67.

Description and Co-Discovery of Gfi1b as a epigenetic modifier protein

Vassen L, Fiolka K and Möröy T
Gfi1b alters histone methylation at target gene promoters and sites of g-satellite containing heterochromation
EMBO Journal, 2006, Jun 7;25(11):2409-19.

Discovery of the role of Gfi1 in inflammation and Toll-like receptor signaling

Sharif-Askari E, Vassen L, Kosan C, Khandanpour C, Gaudreau MC, Heyd F, Okayama T, Jin J, Rojas MEB, Grimes HL, Zeng H and Möröy T.
Zinc finger protein Gfi1 controls the endotoxin-mediated TLR inflammatory response by antagonizing NF-kB p65.
Mol. Cell. Biol., 2010, Aug;30(16):3929-42.

Jin J, Zeng H, Schmid KW, Toetsch M, Uhlig S and Möröy T
The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin mediated inflammatory responses in the lung.
Eur. J. Immunol., 2006, Feb;36(2):421-30.

Requirement of Gfi1 in hematopoietic stem cells, Gfi1 controls stemness and restricts proliferation (204 citations)

Zeng H, Yücel R, Kosan C, Klein-Hitpass L and Möröy T.
Transcription factor Gfi1 regulates self-renewal and long-term engraftment abilities of hematopoietic stem cells by restricting their proliferative potential
EMBO J., 2004, Oct 13;23(20):4116-25

Discovery of the role of Gfi1 in early T-cell development and in beta-selection

Yücel R, Karsunky H, Klein-Hitpass L and Möröy T
The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T-cell progenitors and CD4/CD8 lineage decision in the thymus
J. Exp. Med., 2003 Apr 7;197(7):831-44.

Schmidt T, Karsunky H, Rödel B, Zevnik B, Elsässer HP, Möröy T.
Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with beta-selection.
EMBO J., 1998 Sep 15;17(18):5349-59.

Role of Cyclin E as on oncogene in T-cell lymphomagenesis

Geisen C, Karsunky H, Yücel R and Möröy T.
Loss of p27Kip1 cooperates with cyclin E in T cell lymphomagenesis
Oncogene, 2003, Mar 20;22(11):1724-9.

Geisen C, Möröy T.
The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein.
J Biol Chem. 2002 Oct 18, 277 (42): 39909-39918.

First knockout mouse model of Gfi1 – discovery of its role in neutropenia and inflammation (198 citations)

Karsunky H, Zeng H, Schmidt T, Zevnik B, Kluge R, Schmid KW, Dührsen U and Möröy T.
Inflammatory Reactions and Severe Neutropenia in Mice Lacking the Transcriptional Repressor Gfi-1.
Nature Genetics. 2002, Vol 30 No.3, 295-300

New mouse model for SLE – discovery of the role of DNAse I in SLE (541 citations)

Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Möröy T.
Features of systemic lupus erythematosus in Dnase1-deficient mice.
Nature Genetics. 2000 Jun;25(2):177-81.

Description of the role of PARP in T-cells and in T-cell tumorigenesis

Beneke R and Möröy T.
Inhibition of poly(ADP-ribose)polymerase activity accelerates T-cell lymphomagenesis in p53 deficient mice
Oncogene. 2001 Dec 6; 20(56): 8136-8141

Beneke R, Geisen C, Zevnik B, Küpper JH, Möröy T.
DNA excision repair and DNA damage-induced apoptosis are linked to poly(ADP-ribosyl)ation but have different requirements for p53.
Mol. Cell. Biol. 2000 Sep. 20 (18): 6695-6703

Co-discovery and description of the Gfi1 gene and its potential as a cooperating partner of Myc genes in lymphomagenesis (91 citations)

Schmidt T, Karsunky H, Gau E, Zevnik B, Elsasser HP, Möröy T.
Zinc finger protein GFI-1 has low oncogenic potential but cooperates strongly with pim and myc genes in T-cell lymphomagenesis.
Oncogene. 1998 Nov 19;17(20):2661-7.

Zörnig M, Schmidt T, Karsunky H, Grzeschiczek A, Möröy T.
Zinc finger protein GFI-1 cooperates with myc and pim-1 in T-cell lymphomagenesis by reducing the requirements for IL-2.
Oncogene. 1996 Apr 18;12(8):1789-801.

Demonstration that cell cycle regulatory genes are critical for lymphoid neoplasms (581 citations – 2 papers)

Lovec H, Grzeschiczek A, Kowalski MB, Möröy T.
Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice.
EMBO J. 1994 Aug 1;13(15):3487-95.

Lovec H, Sewing A, Lucibello FC, Muller R, Möröy T.
Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation.
Oncogene. 1994 Jan;9(1):323-6.

Demonstration that Myc family members are oncogenic and cooperate with Pim-1 kinases in lymphomagenesis

Möröy T, Fisher P, Guidos C, Ma A, Zimmerman K, Tesfaye A, DePinho R,
Weissman I, Alt FW.
IgH enhancer deregulated expression of L-myc: abnormal T lymphocyte development and T cell lymphomagenesis.
EMBO J. 1990 Nov;9(11):3659-66.

Möröy T, Verbeek S, Ma A, Achacoso P, Berns A, Alt F.
E mu N- and E mu L-myc cooperate with E mu pim-1 to generate lymphoid tumors at high frequency in double-transgenic mice.
Oncogene. 1991 Nov;6(11):1941-8.

Discovery of a mechanism of malignant transformation by hepatitis B virus using animal model (230 citations 2 papers)

Möröy T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia MA.
Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks.
Nature. 1986 Nov 20-26;324(6094):276-9.

Hsu T, Möröy T, Etiemble J, Louise A, Trepo C, Tiollais P, Buendia MA.
Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma.
Cell. 1988 Nov 18;55(4):627-633