Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways

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 micro-RNAs (miRs) 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 miRs. Most prominently, miR-141 and the miR-200c-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.

Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact

“…In both cohorts, the miR-141/200c cluster showed the strongest upregulation among all miRs and separated T-PLL cases into two major subgroups with normal vs. upregulated expression. Preliminary data revealed a role of this cluster in TGF-b signaling (44) as well as in cell cycle regulation (45). Further perturbations of miR expression include overexpression of miR-223-3p and miR-181a/miR-181 as well as downregulation of the miR-21 and the miR-29 cluster.…”

“…Recently, the miR-ome of T-PLL cells was analyzed by small RNA-seq in two independent cohorts (44,45). T-PLL cells showed a global miR expression signature of ~35 significantly deregulated miRs, resembling the miR expression profile of TCRactivated healthy T-cells (45).…”

“…Recently, the miR-ome of T-PLL cells was analyzed by small RNA-seq in two independent cohorts (44,45). T-PLL cells showed a global miR expression signature of ~35 significantly deregulated miRs, resembling the miR expression profile of TCRactivated healthy T-cells (45). By combining the small RNA-seq with transcriptome sequencing data, regulatory networks involving cell survival signaling and DNA repair pathways were uncovered.…”

“…The functional consequences of these deregulations have yet to be demonstrated in T-PLL. Nevertheless, based on the expression of miR-200a-3p, miR-223-3p, and miR-424-5p, a first overall survival score for T-PLL (miROS-TPLL) was established and might improve clinical stratifications (45).…”

“…Likely, additional perturbations are operational for this TCL1 up /ATM def leukemic precursor to finally escape T-cell homeostatic control. These are acquired by lesions that activate JAK/STAT signaling (43), by miR (processing) deregulations (44,45), by MYC amplification (6,10), and by deregulated epigenetic mechanisms (10,36). To a lesser degree we understand, on which central functional levels, such as TCR-or cytokine signaling or autocrine forward-feeding loops, these (epi)genetic events have a direct or less immediate impact.…”