Large Granular Lymphocyte Expansion in Myeloid Diseases and Bone Marrow Failure Syndromes: Whoever Seeks Finds

Abstract

Large granular lymphocytes (LGL) are lymphoid cells characterized by either a T-cell or a natural killer phenotype whose expansion may be reactive to toxic, infectious, and neoplastic conditions, or result from clonal selection. Recently, the higher attention to LGL clones led to their detection in many clinical conditions including myeloid neoplasms and bone marrow failures. In these contexts, it is still unclear whether LGL cells actively contribute to anti-stem cell autoimmunity or are only a reaction to dysplastic/leukemic myelopoiesis. Moreover, some evidence exists about a common clonal origin of LGL and myeloid clones, including the detection of STAT3 mutations, typical of LGL, in myeloid precursors from myelodysplastic patients. In this article we reviewed available literature regarding the association of LGL clones with myeloid neoplasms (myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemias) and bone marrow failures (aplastic anemia and pure red cell aplasia, PRCA) focusing on evidence of pathogenic, clinical, and prognostic relevance. It emerged that LGL clones may be found in up to one third of patients, particularly those with PRCA, and are associated with a more cytopenic phenotype and good response to immunosuppression. Pathogenically, LGL clones seem to expand after myeloid therapies, whilst immunosuppression leading to LGL depletion may favor leukemic escape and thus requires caution.

Low-Risk Myelodysplastic Syndrome Revisited: Morphological, Autoimmune, and Molecular Features as Predictors of Outcome in a Single Center Experience

“…This paradox may be speculatively related to the transition of the immune system from pro-inflammatory/pro-apoptotic in early MDS to tumor permissive facilitating leukemic progression in the late stage ( 26 , 42 ). Indeed, somatic mutations may be present not only in the myeloid compartment but also in the immunologic microenvironment, as described for MDS, but also for aplastic anemia and other autoimmune diseases ( 43 – 45 ). Lymphoid clonality, particularly of CD8+ T-cells and large granular lymphocytes (LGL) in patients with bone marrow failure, may represent both a player in inducing apoptosis of marrow precursors and a result of chronic stimulation via exposure of self-antigens resulting from ineffective erythropoiesis.…”

“…Lymphoid clonality, particularly of CD8+ T-cells and large granular lymphocytes (LGL) in patients with bone marrow failure, may represent both a player in inducing apoptosis of marrow precursors and a result of chronic stimulation via exposure of self-antigens resulting from ineffective erythropoiesis. In this view, it has been reported that STAT3-mutant LGL clones may facilitate bone marrow failure in a subset of aplastic anemia patients and may be potentially amenable to immunosuppressive treatment ( 44 , 45 ).…”

Distinguishing STAT3/STAT5B-mutated large granular lymphocyte leukemia from myeloid neoplasms by genetic profiling

“…1,[4][5][6] Compounding the issue of specificity is that clonal LGL expansions are frequently observed in MNs and frequent STAT3/5B mutations have been reported in MNs with associated LGL expansion. 4,7,8 Rarely, have LGLLs been diagnosed concomitantly in patients with otherwise typical MNs. 9,10 Based on morphology, flow cytometry, and T-cell clonality studies alone, it may be challenging to classify a marrow process with both LGL expansion [11][12][13][14] and morphologic dysplasia 7 (Fig.…”

“…4,7,8 Rarely, have LGLLs been diagnosed concomitantly in patients with otherwise typical MNs. 9,10 Based on morphology, flow cytometry, and T-cell clonality studies alone, it may be challenging to classify a marrow process with both LGL expansion [11][12][13][14] and morphologic dysplasia 7 (Fig. S1) as an LGLL versus an MN or both.…”

“…S1) as an LGLL versus an MN or both. 7 To present further challenges, both manifest with varying degrees of cytopenias and heterogenous lymphocyte counts, and are frequently found in the elderly. Genetic profiling using NGS supports an accurate diagnosis in challenging cases and is an area of investigation as cytopenic patients with different underlying causes require different therapy.…”