NK-type large granular lymphocyte leukemia comes of age

Abstract

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.

Figure 1

Differentiation stages of human NK cells, including their functional activities over time during cell maturation. The box on the right lists markers that characterize normal mature NK cells (CD16+), corresponding to NK cells at the final stage of maturation in peripheral blood. For reference ranges, see , , and .

Figure 2

Flow cytometry plots of three representative NK‐cell expansions. Panels (A)–(C) show a representative NK immunophenotype in NK‐LGLL, observed on total lymphocytes: an increase in the CD16+/CD3− (84%) population (A), CD56+ (84%) population (B), and a partial CD57+ (30%) population (C). Panels (D)–(I) show two types of KIR restriction observed in clonal NK cells (gated on CD16+ cells). Panels (D)–(F) for patient 1 demonstrate KIR restriction due to the expression of a unique KIR: absence of CD158a (D) and CD158e (F), and expression of CD158b > 90% of NK cells (E). Panels (G)–(I) relate to patient 2 and show KIR restriction due to the absence of all KIRs: CD158a (G), CD158b (H), and CD158e (I). Panels (J)–(L) display a polyclonal pattern, characterized by expression of all KIRs, at variable frequencies with the predominance of CD158b. The expression of all the three KIRs can be detected in both normal NK cells and non‐restricted polyclonal NK cell expansions. The physiological reference range expected for KIRs (CD158a/b/e) is reported in the box of Figure 1.

Figure 3

Morphological appearance of LGLL in peripheral blood. May‐Grunwald Giemsa staining 1000×.

Figure 4

Different phases of NK‐LGLL development. Three main steps are shown: (1) the polyclonal expansion, (2) the emergence of clonal NK cells, mainly driven by somatic mutations (indicated by the lightning bolts), and (3) disease progression to fully developed NK‐LGLL. The role of the microenvironment is covered in Figure 5. The bottom right box highlights the most prevalent phenotype of NK‐LGLL. Notably, within the group of patients harboring a CD56neg/dimCD16high NK cell clone (the most common phenotype in NK‐LGLL), clonal NK cells may be either CD57− or CD57+. CD57− NK cells are cytotoxic, many carry STAT3 mutations, and are associated with symptomatic patients. CD57+ NK cells exhibit memory‐like properties and are linked to an indolent disease course.

Figure 5

Schematic representation of intrinsic and extrinsic factors involved in the etiopathogenesis of NK‐LGLL. See text for details. IL, interleukin; LGL, large granular lymphocyte.