Universität zu Köln

Braun, Till, Glass, Markus ORCID: 0000-0003-2718-8907, Wahnschaffe, Linus, Otte, Moritz, Mayer, Petra, Franitza, Marek, Altmuller, Janine ORCID: 0000-0003-4372-1521, Hallek, Michael ORCID: 0000-0002-7425-4455, Huttelmaier, Stefan, Schrader, Alexandra and Herling, Marco (2022). Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways. Haematologica, 107 (1). S. 187 - 201. PAVIA: FERRATA STORTI FOUNDATION. ISSN 0390-6078

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Abstract

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic mature T-cell malignancy. It typically presents with exponentially rising lymphocyte counts, splenomegaly, and bone marrow infiltration. Effective treatment options are scarce and a better understanding of T-PLL's pathogenesis is desirable. Activation of the TCL1 proto-oncogene and loss-of-function perturbations of the tumor suppressor ATM are T-PLL's genomic hallmarks. The leukemic cell reveals a phenotype of active T-cell receptor (TCR) signaling and aberrant DNA damage responses. Regulatory networks based on the profile of microRNA (miR) have not been described for T-PLL. In a combined approach of small-RNA and transcriptome sequencing in 46 clinically and moleculary well-characterized T-PLL, we identified a global T-PLL-specific miR expression profile that involves 34 significantly deregulated miR species. This pattern strikingly resembled miR-ome signatures of TCR-activated T cells. By integrating these T-PLL miR profiles with transcriptome data, we uncovered regulatory networks associated with cell survival signaling and DNA damage response pathways. Despite a miR-ome that discerned leukemic from normal T cells, there were also robust subsets of T-PLL defined by a small set of specific miR. Most prominently, miR-141 and the miR200c-cluster separated cases into two major subgroups. Furthermore, increased expression of miR-223-3p as well as reduced expression of miR-21 and the miR-29 cluster were associated with more activated T-cell phenotypes and more aggressive disease presentations. Based on the implicated pathobiological role of these miR deregulations, targeting strategies around their effectors appear worth pursuing. We also established a combinatorial miR-based overall survival score for T-PLL (miROS-T-PLL), that might improve current clinical stratifications.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Braun, Till UNSPECIFIED UNSPECIFIED UNSPECIFIED Glass, Markus UNSPECIFIED orcid.org/0000-0003-2718-8907 UNSPECIFIED Wahnschaffe, Linus UNSPECIFIED UNSPECIFIED UNSPECIFIED Otte, Moritz UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmuller, Janine UNSPECIFIED orcid.org/0000-0003-4372-1521 UNSPECIFIED Hallek, Michael UNSPECIFIED orcid.org/0000-0002-7425-4455 UNSPECIFIED Huttelmaier, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-669757
DOI:	10.3324/haematol.2020.267500
Journal or Publication Title:	Haematologica
Volume:	107
Number:	1
Page Range:	S. 187 - 201
Date:	2022
Publisher:	FERRATA STORTI FOUNDATION
Place of Publication:	PAVIA
ISSN:	0390-6078
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; TCL1 EXPRESSION; PROGRESSION; ARGONAUTE; MUTATIONS Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66975