Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.

Clonal expansions of large granular lymphocytes (LGL) have been reported in a wide spectrum of conditions, with LGL leukemia (LGLL) being the most extreme. However, the boundaries between LGLL and LGL clones are often subtle, and both conditions can be detected in several clinical scenarios, particularly in patients with cytopenias. The intricate overlap of LGL clonal expansion with other disease entities characterized by unexplained cytopenias makes their classification challenging. Indeed, precisely assigning whether cytopenias might be related to inadequate hematopoiesis (i.e., LGL as a marginal finding) rather than immune-mediated mechanisms (i.e., LGLL) is far from being an easy task. As LGL clones acquire different pathogenetic roles and relevance according to their diverse clinical settings, their detection in the landscape of bone marrow failures and myeloid neoplasms has recently raised growing clinical interest. In this regard, the current availability of different diagnostic techniques, including next generation sequencing, shed light on the relationship between LGL clones and cytopenias, paving the way towards a better disease classification for precision medicine treatments. Herein, we discuss the clinical relevance of LGL clones in the diagnostic algorithm to be followed in patients presenting with cytopenias, offering a foundation for rational management approaches.

NK‐large granular lymphocyte leukemia (NK‐LGLL) is a lymphoid malignancy driven by constitutive activation of cellular pathways and chronic inflammation, underscoring the central role of the microenvironment in the disease's pathogenesis. Patients with NK‐LGLL typically present with an expansion of mature NK cells displaying large granular lymphocyte morphology, a restricted killer Immunoglobulin‐like receptor pattern and genetic lesions, including TET2, CCL22, and STAT3 mutations. NK‐LGLL generally follows an indolent clinical course and rarely progresses to a stage requiring treatment. The rarity of the disease has significantly hampered precise diagnosis, a deeper understanding of its pathogenesis, the assessment of appropriate clinical trials, and even its classification. This review aims to present the latest insights into genetic, biological, and clinical features of this disorder. In particular, recent advances in genetics and epigenetics, along with emerging knowledge into the role of microenvironment, have uncovered new vulnerabilities in leukemic cells. These findings may have a meaningful impact on defining genomic‐driven disease subsets and hold promise for improving outcomes in large granular lymphocyte leukemia patients through the development of personalized, innovative therapies.

Finding an effective treatment for T-PLL patients remains a significant challenge. Alemtuzumab, currently the gold standard, is insufficient in managing the aggressiveness of the disease in the long term. Consequently, numerous efforts are underway to address this unmet clinical need. The rarity of the disease limits the ability to conduct robust clinical trials, making in silico, ex vivo, and in vivo drug screenings essential for designing new therapeutic strategies for T-PLL. We conducted a drug repurposing analysis based on T-PLL gene expression data and identified proteasome inhibitors (PIs) as a promising new class of compounds capable of reversing the T-PLL phenotype. Treatment of ex vivo T-PLL cells with Bortezomib and Carfilzomib, two PI compounds, supported this hypothesis by demonstrating increased apoptosis in leukemic cells. The current lack of a suitable in vitro model for the study of T-PLL prompted us to perform similar experiments in the SUP-T11 cell line, validating its potential by showing an increased apoptotic rate. Taken together, these findings open new avenues for investigating the molecular mechanisms underlying the efficacy of PI in T-PLL and expand the spectrum of potential therapeutic strategies for this highly aggressive disease.

Background/Objectives: Identifying molecular liabilities and understanding disease heterogeneity are prerequisites for advancing therapies in T-cell prolymphocytic leukemia (T-PLL), a rare T-cell malignancy with a poor prognosis. Methods: RNA-seq profiling of T-PLL samples (n = 10) and the normal counterpart (n = 5) allowed us to report gene expression and pathway alterations in malignant cells, revealing that non-coding, antisense and circular RNA expression is profoundly altered in T-PLL. Results: T-PLL displayed activation of several oncogenic pathways, particularly PI3K/AKT/mTOR and Wnt, suppression of healthy T-cell activities and cell death escape. Tumor suppressor lncRNAs (NEAT1, MIAT and LUCAT1) with reduced expression and upregulated oncogenic pro-proliferative lncRNAs (FIRRE, TERC, XIST and PVT1) were identified. CircRNAs ectopically expressed in T-PLL included circSEMA4B and circSATB1, linked to the Wnt pathway, circFIRRE and oncogenic circPVT1 and circFKBP5. Focusing on five genes with validated recurrent oncogenic variants (STAT5B, JAK3, ATM, KMT2C, and ARID1A), we investigated genotype/phenotype relations. A multiple predictor linear model suggested potential links between driver variants and alterations in gene and circRNA expression, including association between STAT5B mutations and LTF upregulation, JAK3 lesions and increased PLXNA4 expression along with CCR4 suppression. Conclusions: Our transcriptomic profiling and genotype–phenotype association analysis identified specific genes, non-coding RNAs, pathways and candidate genotype-associated transcriptional signatures that warrant further investigation as potential targets for the development of new therapeutic approaches for this rare and heterogeneous malignancy.