Simple SummaryT-prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. A better understanding of this chemotherapy-refractory disease is highly warranted to identify novel treatment strategies. We previously identified an elevated expression of the miR-141/200c cluster in T-PLL cells. Here, we show a pro-proliferative effect of miR-141/200c in mature T-cell lymphoma cell lines. We further characterize a miR-141/200c-driven transcriptome, entailing altered expression of genes involved in pathways regulating cell survival and differentiation. Among those, we identifiedSTAT4as a miR-141/200c target gene, with lowSTAT4expression being associated with an immature phenotype of T-PLL cells and with shortened overall survival of T-PLL patients. Overall, we present an oncogenic miR-141/200c-STAT4 signaling route in T-PLL, demonstrating, for the first time, a role of non-protein-coding genes in the leukemogenesis of this devastating disease.AbstractT-prolymphocytic leukemia (T-PLL) is a rare and mature T-cell malignancy with characteristic chemotherapy-refractory behavior and a poor prognosis. Molecular concepts of disease development have been restricted to protein-coding genes. Recent global microRNA (miR) expression profiles revealed miR-141-3p and miR-200c-3p (miR-141/200c) as two of the highest differentially expressed miRs in T-PLL cells versus healthy donor-derived T cells. Furthermore, miR-141/200c expression separates T-PLL cases into two subgroups with high and low expression, respectively. Evaluating the potential pro-oncogenic function of miR-141/200c deregulation, we discovered accelerated proliferation and reduced stress-induced cell death induction upon stable miR-141/200c overexpression in mature T-cell leukemia/lymphoma lines. We further characterized a miR-141/200c-specific transcriptome involving the altered expression of genes associated with enhanced cell cycle transition, impaired DNA damage responses, and augmented survival signaling pathways. Among those genes, we identifiedSTAT4as a potential miR-141/200c target. LowSTAT4expression (in the absence of miR-141/200c upregulation) was associated with an immature phenotype of primary T-PLL cells as well as with a shortened overall survival of T-PLL patients. Overall, we demonstrate an aberrant miR-141/200c-STAT4 axis, showing for the first time the potential pathogenetic implications of a miR cluster, as well as of STAT4, in the leukemogenesis of this orphan disease.