Universität zu Köln

Patil, Paurnima, Cieslak, Agata ORCID: 0000-0003-1015-9448, Bernhart, Stephan H., Toprak, Umut H., Wagener, Rabea, Lopez, Cristina ORCID: 0000-0001-6644-1659, Wiehle, Laura ORCID: 0000-0001-6081-3925, Bens, Susanne, Altmueller, Janine, Franitza, Marek, Scholz, Ingrid, Jayne, Sandrine, Ahearne, Matthew J., Scheffold, Annika, Jebaraj, Billy M. C., Schneider, Christof, Costa, Dolors, Braun, Till, Schrader, Alexandra, Campo, Elias, Dyer, Martin J. S., Nuernberg, Peter, Duerig, Jan, Johansson, Patricia, Boettcher, Sebastian, Schlesner, Matthias, Herling, Marco, Stilgenbauer, Stephan, Macintyre, Elizabeth and Siebert, Reiner (2020). Reconstruction of rearranged T-cell receptor loci by whole genome and transcriptome sequencing gives insights into the initial steps of T-cell prolymphocytic leukemia. Gene Chromosomes Cancer, 59 (4). S. 261 - 268. HOBOKEN: WILEY. ISSN 1098-2264

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Abstract

T-cell prolymphocytic leukemia (T-PLL) is an aggressive tumor with leukemic presentation of mature T-lymphocytes. Here, we aimed at characterizing the initial events in the molecular pathogenesis of T-PLL and particularly, at determining the point in T-cell differentiation when the hallmark oncogenic events, that is, inv(14)(q11q32)/t(14;14)(q11;q32) and t(X;14)(q28;q11) occur. To this end, we mined whole genome and transcriptome sequencing data of 17 and 11 T-PLL cases, respectively. Mapping of the 14q32.1 locus breakpoints identified only TCL1A, which was moreover significantly overexpressed in T-PLL as compared to benign CD4+ and CD8+ T-cells, as the only common oncogenic target of aberrations. In cases with t(14;14), the breakpoints mapped telomeric and in cases with inv(14) centromeric or in the 3 '-untranslated region of TCL1A. Regarding the T-cell receptor alpha (TRA) locus-TCL1A breakpoint junctions, all 17 breakpoints involved recombination signal sequences and 15 junctions contained nontemplated (N-) nucleotides. All T-PLL cases studied carried in-frame TRA rearrangements on the intact allele, which skewed significantly toward usage of distal/central TRAV/TRAJ gene segments as compared to the illegitimate TRA rearrangements. Our findings suggest that the oncogenic TRA-TCL1A/MTCP1 rearrangements in T-PLL occur during opening of the TRA locus, that is, during the progression from CD4+ immature single positive to early double positive thymocyte stage, just before physiologic TCL1A expression is silenced. The cell carrying such an oncogenic event continues maturation and rearranges the second TRA allele to achieve a functional T-cell receptor. Thereafter, it switches off RAG and DNTT expression in line with the mature T-cell phenotype at presentation of T-PLL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Patil, Paurnima UNSPECIFIED UNSPECIFIED UNSPECIFIED Cieslak, Agata UNSPECIFIED orcid.org/0000-0003-1015-9448 UNSPECIFIED Bernhart, Stephan H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toprak, Umut H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Rabea UNSPECIFIED UNSPECIFIED UNSPECIFIED Lopez, Cristina UNSPECIFIED orcid.org/0000-0001-6644-1659 UNSPECIFIED Wiehle, Laura UNSPECIFIED orcid.org/0000-0001-6081-3925 UNSPECIFIED Bens, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Scholz, Ingrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Jayne, Sandrine UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahearne, Matthew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheffold, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Jebaraj, Billy M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Christof UNSPECIFIED UNSPECIFIED UNSPECIFIED Costa, Dolors UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Till UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Campo, Elias UNSPECIFIED UNSPECIFIED UNSPECIFIED Dyer, Martin J. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Duerig, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Johansson, Patricia UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettcher, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlesner, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Macintyre, Elizabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, Reiner UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-126877
DOI:	10.1002/gcc.22821
Journal or Publication Title:	Gene Chromosomes Cancer
Volume:	59
Number:	4
Page Range:	S. 261 - 268
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-2264
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language V(D)J RECOMBINATION; RAG PROTEINS; EXPRESSION; GENE; TCL1; MUTATIONS; THYMOCYTES Multiple languages Oncology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12687