Sokol, Lubomir

BackgroundMycosis fungoides (MF) and Sézary Syndrome (SS) are clinically distinct cutaneous T‐cell lymphomas with strikingly similar morphologic and phenotypic features. Prior studies have suggested phenotypic differences based on markers of antigen experience, suggesting a different cell of origin.MethodsSeventy‐nine involved peripheral blood or bone marrow samples from 33 patients with SS and 19 patients with MF were studied by 10‐color flow cytometry, including CD62L, CD45RA, CCR4, and PD‐1. Gated tumor events were classified as naïve (TN), central memory (TCM), effector memory (TEM), or effector memory with reacquired CD45RA (TEMRA); based on CD62L+/CD45RA+, CD62L+/CD45RA−, CD62L−/CD45RA−, or CD62L−/CD45RA+ phenotype, respectively. Sequential specimens were compared to assess for phenotypic stability.ResultsThe naïve/memory phenotype of the neoplastic T‐cells was markedly heterogeneous, with a dominant TN, TCM, TEM, or TEMRA subset on 11 (14%), 32 (41%), 30 (38%), and 6 (8%) cases, respectively. There was no correlation between the diagnosis of MF or SS and putative cell of origin (P = 0.4). Overexpression of CCR4 and PD1 was observed in most cases, with higher intensity in SS compared to MF. The naïve/memory phenotype remained the same for 10 patients up to 273 days after the initial analysis; while on six patients, the naïve/memory phenotype was different from the original phenotype.ConclusionsBoth SS and MF can have phenotypic features of any of the major naïve/memory T‐cell subsets, which questions the current principle of “cell‐of‐origin” distinction between SS and MF. Phenotypic shifts within these subsets are common, suggesting a functional state rather than a cell‐of‐origin surrogate. © 2018 International Clinical Cytometry Society

Nonhepatosplenic/noncutaneous γδ peripheral T-cell lymphoma (NHNCγδ PTCL) represents a miscellaneous group of unrelated T-cell lymphomas of which only isolated cases have been reported. We describe two cases of transformation from T-lymphoblastic leukemia/lymphoma to NHNCγδ PTCL. Transformation into more aggressive disease is a rare event in T-cell lineage-derived hematologic malignancies compared to B-cell neoplasms. Nevertheless, both of our cases involved relapse as PTCL manifested with skin involvement and an overt shift from blastic morphology to large granular leukemia-like mature T cells. Among other notable molecular characteristics, expression of immature markers such as TdT was lost in both cases. Based on cytogenetics, phenotype, and morphology, both patients represent a novel phenomenon of clonal transformation from T-ALL to PTCL which has rarely been reported in the literature. Such transformation may carry important diagnostic and biological implications.

Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Acα, which are coregulators of the G 2 -M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G 2 arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Ac α gene expression recapitulated del(5q) susceptibility to lenalidomide with induction of G 2 arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Acα phosphatases in the selective drug sensitivity of del(5q) MDS.