Marco Herling / Elena Vasyutina - A 5

Context-specific mechanisms of the TCL1 oncogene in T- and B-cell leukemias

Research

Our group aims at a refined molecular understanding of the oncogene T-cell leukemia 1 (TCL1), particularly in B-cell tumors represented by chronic lymphocytic leukemia (CLL) and in T-cell neoplasms, represented by T-cell prolymphocytic leukemia (T-PLL). As the most prevalent B-cell leukemia of adults in the Western hemisphere, CLL is characterized by a marked biologic diversity. Disease subsets with an unfavorable prognosis carry defining aberrations, most prominently involving the TP53 tumor suppressor locus at chromosome 17p. Recently, the panel of “risk” factors in CLL was extended by data on the proto-oncogene TCL1. Importantly, TCL1 carries prognostic information in both CLL and T-PLL, the latter representing the most frequent mature T-cell leukemia. In previous work we showed TCL1 overexpression in ≈80% of T-PLL and CLL, and that variably high levels correlate with an inferior clinical outcome in both entities. While the recurrent genomic aberrations (e.g. inv(14) or t(14;14)) are responsible for the abnormal TCL1 expression in T-PLL, the causes of high TCL1 in CLL are much more diverse, and likely not fully understood. Moreover, our concept of the oncogenic mechanisms of TCL1 is incomplete.

We employ quantitative mass spectrometry based proteomics to address the underlying molecular mechanisms of B- and T- cell hematologic tumors and to tackle the intrinsic and extrinsic control of cell proliferation and tissue invasion. Building up on our data, we postulate that the constitutional kinetics, including (biased) substrate profiles of TCL1-bound protein complexes are central for the transforming activities in the context of complex-inducing stimuli, e.g. antigen-receptor, DNA damage, cell-cycle activation, including specifics of additional ‘contexts’ such as lineage (B- vs T-) or leukemic stage.

Publications

Schrader A, Crispatzu G, Oberbeck S, Mayer P, Pützer S, Jan von J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmüller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brümmendorf TH, Nürnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, Herling M. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 2018 Feb.;9(1):697.

Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlößer HA, Odenthal M, Büttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, Ullrich RT. Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res. 2018 May 18. [Epub ahead of print].

Knittel G, Rehkämper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, Al-Baldawi Y, Al-Maarri M, Cun Y, Fedorchenko O, Riabinska A, Beleggia F, Nguyen P-H, Wunderlich FT, Ortmann M, Montesinos-Rongen M, Tausch E, Stilgenbauer S, P Frenzel L, Herling M, Herling C, Bahlo J, Hallek M, Peifer M, Buettner R, Persigehl T, Reinhardt HC. Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun 2017 Jul.;8(1):153.

Andersson EI, Pützer S, Yadav B, Dufva O, Khan S, He L, Sellner L, Schrader A, Crispatzu G, Oleś M, Zhang H, Adnan-Awad S, Lagström S, Bellanger D, Mpindi JP, Eldfors S, Pemovska T, Pietarinen P, Lauhio A, Tomska K, Cuesta-Mateos C, Faber E, Koschmieder S, Brümmendorf TH, Kytölä S, Savolainen E-R, Siitonen T, Ellonen P, Kallioniemi O, Wennerberg K, Ding W, Stern MH, Huber W, Anders S, Tang J, Aittokallio T, Zenz T, Herling M, Mustjoki S. Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. Leukemia 2017 Aug.; 32(3):774-787.

Coppe A, Andersson EI, Binatti A, Gasparini VR, Bortoluzzi S, Clemente M, Herling M, Maciejewski J, Mustjoki S, Bortoluzzi S. Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach. Leukemia 2017 May;31(5):1243–1246.

Crispatzu G, Kulkarni P, Toliat MR, Nürnberg P, Herling M, Herling CD, Frommolt P. Semi-automated cancer genome analysis using high-performance computing. Hum. Mutat. 2017 Jun.; 38(10):1325-1335.

Rengstl B, Kim S, Döring C, Weiser C, Bein J, Bankov K, Herling M, Newrzela S, Hansmann M-L, Hartmann S. Small and big Hodgkin-Reed-Sternberg cells of Hodgkin lymphoma cell lines L-428 and L-1236 lack consistent differences in gene expression profiles and are capable to reconstitute each other. PLoS ONE 2017;12(5): e0177378.

Shimabukuro-Vornhagen A, García-Márquez M, Fischer RN, Iltgen-Breburda J, Fiedler A, Wennhold K, Rappl G, Abken H, Lehmann C, Herling M, Wolf D, Fätkenheuer G, Rubbert-Roth A, Hallek M, Theurich S, Bergwelt-Baildon von M. Antigen-presenting human B cells are expanded in inflammatory conditions. J. Leukoc. Biol. 2017 Feb.;101(2):577–587.

Bachy E, Urb M, Chandra S, Robinot R, Bricard G, de Bernard S, Traverse-Glehen A, Gazzo S, Blond O, Khurana A, Baseggio L, Heavican T, Ffrench M, Crispatzu G, Mondière P, Schrader A, Taillardet M, Thaunat O, Martin N, Dalle S, Le Garff-Tavernier M, Salles G, Lachuer J, Hermine O, Asnafi V, Roussel M, Lamy T, Herling M, Iqbal J, Buffat L, Marche PN, Gaulard P, Kronenberg M, Defrance T, Genestier L. CD1d-restricted peripheral T cell lymphoma in mice and humans. J Exp Med. 2016 May 2;213(5):841-57.

Lohmann G, Vasyutina E, Bloehdorn J, Reinart N, Schneider JI, Babu V, Knittel G, Crispatzu G, Mayer P, Prinz C, Muenzner JK, Biersack B, Efremov DG, Chessa L, Herling CD, Stilgenbauer S, Hallek M, Schobert R, Reinhardt HC, Schumacher B, Herling M. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia 2016 Oct.; 31(5):1177-1186.

Stiefelhagen M, Gigel C, Vasyutina E, Möllmann M, Breuer A, Mayer P, Dürig J, Herling M. Activity of the CD40 antagonistic antibody lucatumumab - insights from CLL-niche mimicking xenografts and fludarabine combinations. Leuk. Lymphoma 2016 Jan. :1–4.

Reiners KS, Shatnyeva O, Vasyutina E, Bösl T, Hansen HP, Hallek M, Herling M, Pogge von Strandmann E. Extracellular vesicles released from chronic lymphocytic leukemia cells exhibit a disease relevant mRNA signature and transfer mRNAs to bystander cells. Haematologica 2016 Nov.; 15(5):971-984.

Vasyutina E, Boucas JM, Bloehdorn J, Aszyk C, Crispatzu G, Stiefelhagen M, Breuer A, Mayer P, Lengerke C, Döhner H, Beutner D, Rosenwald A, Stilgenbauer S, Hallek M, Benner A, Herling M. The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia 2015 May; 29(10):2003-14.


Dr. Marco Herling

Dept. I of Internal Medicine / RG location - CECAD Building

Dr. Marco Herling

Principal Investigator A 5

marco.herling@uk-koeln.de

Work +49 221 478 5194

Building 15
Kerpener Straße 62
50937 Cologne

http://herlinglab.com/

Publications - Marco Herling

Link to PubMed


Dr. Elena Vasyutina

Dept. I of Internal Medicine / RG location - CECAD Building

Dr. Elena Vasyutina

Co-Principal Investigator A 5

elena.vasyutina@uk-koeln.de

Work +49 221 478 4130

Building 15
Kerpener Straße 62
50937 Cologne

Publications - Elena Vasyutina

Link to PubMed

Group Members

Till Braun (PhD student)
Jana von Jan (PhD student)
Qu Jiang (PhD student)
Dennis Jungherz (Master Student)
Petra Mayer (technical assistent)
Sebastian Oberbeck (PhD student)
Alexandra Schrader (PostDoc)
Johanna Stachelscheid (PhD student)
Linus Wahnschaffe (PhD student)
Deyu Zou (PhD student)