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Chronic Lymphocytic Leukemia
The miR-200c/141-ZEB2-TGFb axis is aberrant in human T-cell prolymphocytic leukemia
Stefan J. Erkeland,1 Christiaan J. Stavast,1 Joyce Schilperoord-Vermeulen,1 Giada Dal Collo,1 Harmen J.G. van de Werken,1,2 Leticia G. Leon,1
Antoinette van Hoven-Beijen,1 Iris van Zuijen,1 Yvonne M. Mueller,1
Eric M. Bindels,3 Dick de Ridder,4 Mies C. Kappers-Klunne,3 Kirsten van Lom,3 Vincent H.J. van der Velden1 and Anton W. Langerak1
1Department of Immunology, Erasmus MC, University Medical Center, Rotterdam; 2Cancer Computational Biology Center, Cancer Institute, Erasmus MC, University Medical Center, Rotterdam; 3Department of Hematology, Erasmus MC, University Medical Center, Rotterdam and 4Bioinformatics Group, Wageningen University, Wageningen, the Netherlands
ABSTRACT
T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL con- sists of phenotypic and/or genotypic subgroups that may explain the heterogeneity of the disease. Multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups, and no clear T-cell receptor a or b CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of microRNA (miRNA) is aberrant and often heterogeneous in T-PLL. We identified 35 miRNA that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR- 200c/141 and miR-181a/181b expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 correlated with down- regulation of their targets ZEB2 and TGFbR3 and aberrant TGFb1- induced phosphorylated SMAD2 (p-SMAD2) and p-SMAD3, indicating that the TGFb pathway is affected in T-PLL. Our results thus highlight the potential role for aberrantly expressed oncogenic miRNA in T-PLL and pave the way for new therapeutic targets in this disease.
Introduction
T-cell prolymphocytic leukemia (T-PLL) is a relatively rare disease accounting for approximately 2% of mature lymphocytic leukemia patients older than 30 years.1 T-PLL is characterized by an uncontrolled expansion of malignant, mature, post- thymic T lymphocytes in the bone marrow (BM), lymph nodes, liver and spleen, resulting in hepato-splenomegaly, lymphadenopathy, skin lesions and a high leukocyte count. Whole-transcriptome analysis of T-PLL cells revealed that the most significantly deregulated genes are involved in T-cell receptor signaling, cytokine signaling and p53-controlled apoptosis.2 In addition, frequent recurrent mutations in DNA damage repair/tumor suppressor genes (e.g., ATM, TP53, MSH3, MSH6, SAMHD1, PARP10, HERC1, HERC2), and oncogenes (JAK1 and JAK3) have been described in T-PLL.3,4 The majority of T-PLL cases exhibit a com- plex karyotype.3 Many distinct chromosomal abnormalities, including common chromosomal translocations involving chromosome 8, 11 and 14, deletions in 11q, 8p and 7q34q36 and gains of 8q and 8p11p12 have been reported.2,5 However, most T-PLL cases have abnormalities of chromosome 14, of which inv(14)(q11q32) and t(14:14)(q11;q32) are found most frequently.5 Chromosome 14 abnormalities bring the T-cell leukemia/lymphoma 1A (TCL1A, TCL1) oncogene on chromo-
Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):143-153
Correspondence:
STEFAN J. ERKELAND
s.erkeland@erasmusmc.nl
ANTON W. LANGERAK
a.langerak@erasmusmc.nl
Received: June 18, 2020. Accepted: January 22, 2021. Pre-published: February 18, 2021.
https://doi.org/10.3324/haematol.2020.263756 ©2022 Ferrata Storti Foundation
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