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The article discusses research which investigated large granular lymphocyte (LGL) leukemia diagnosis, conducted by B. Bockorny and colleagues, published within the issue. Topics explored include the clinical characteristics of LGL leukemia, the hematological conditions like neutropenia and hemolytic anemia that LGL leukemia patients tend to suffer, and the effectiveness of peripheral blood immunophenotyping as a diagnostic tool for the condition.

In this article the authors comment on the study by Fedele and colleagues on the expansion of cytotoxic T lymphocyte (CTL) in allogeneic hematopoietic stem cell transplant recipients. The authors predict that the platelet-derived growth factor receptor (PDGFR) and receptor tyrosine kinases (RTKs) may play a role in large granular lymphocyte (LGL) leukemia patients. However, there is an expansion of LGLs in chronic myeloid leukemia (CML) patients which are treated wtih RTK inhibitors.

In this article the authors discuss the effects of tyrosine kinase inhibitors (TKIs) in treating patients with chronic myeloid leukemia (CML), and relates it to the study of J. J. Powers and colleagues on the correlation of large granular lymphocytes (LGL) expansion in CML patients treated with TKIs. They state that TKIs have been used to target breakpoint cluster region-abelson (BCR-ABL) protein fusion. The study showed that LGL population was only identified in patients treated with dasatinib.

Large granular lymphocyte (LGL) leukemia is a rare disorder of cytotoxic lymphocytes. LGL cells play an integral role in the immune system and are divided into two major lineages of CD3−natural killer (NK) cells and CD3++ T cells that circulate throughout the blood in search of infected cells, in which they will make contact through a receptor ligand and induce cell death. LGL cells are also programmed to undergo apoptosis after contact with an infected target cell; however, they continue to survive in individuals with LGL leukemia. This unchecked proliferation and cytotoxicity of LGLs in patients results in autoimmunity or malignancy. Rheumatoid arthritis is the most common autoimmune condition seen in individuals with LGL leukemia; however, LGL leukemia is associated with a wide spectrum of other autoimmune diseases. Patients may also suffer from other hematological conditions including hemolytic anemia, pure red cell aplasia, and neutropenia, which lead to recurrent bacterial infections. Currently, the only established treatment involves a low dose of an immunosuppressive regimen with methotrexate, in which 40-50% of patients are either resistant or do not respond. In order to establish new therapeutics it is important to understand the current state of LGL leukemia both in the clinic and in basic research. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell leukemia is characterized by clonal expansion of CD3 − NK cells and comprises both chronic and aggressive forms. Currently no effective treatment exists, thus providing a need for identification of novel therapeutics. Lipidomic studies revealed a dysregulated sphingolipid metabolism as evidenced by decreased levels of overall ceramide species and increased levels of cerebrosides in leukemic NK cells, concomitant with increased glucosylceramide synthase (GCS) expression. GCS, a key enzyme of this pathway, neutralizes pro-apoptotic ceramide by transfer of a uridine diphosphate (UDP)-glucose. Thus, we treated both rat and human leukemic NK cells in combination with: (1) exogenous C6-ceramide nanoliposomes in order to target mitochondria and increase physiological pro-apoptotic levels of long chain ceramide, and (2) 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), an inhibitor of GCS. Co-administration of C6-ceramide nanoliposomes and PPMP elicited an increase in endogenous long-chain ceramide species, which led to cellular apoptosis in a synergistic manner via the mitochondrial intrinsic cell death pathway in leukemic NK cells. [ABSTRACT FROM AUTHOR]