Chronic lymphocytosis of large granular lymphocytes (LGL) associated with neutropenia and/or anemia was first described in 1985 to be the result of clonal cytogenetic abnormalities. These LGL proliferations are now recognized as being clonally derived from either CD3- or CD3+ LGL, and the resulting diseases are designated natural killer (NK)-LGL leukemia and T-LGL leukemia, respectively. Peripheral elimination of normal activated NK- and T-LGL cells occurs through apoptosis by a Fas (CD95)-mediated pathway. Therefore, the central hypothesis of Dr. Epling-Burnette and her colleagues is that the LGL cells accumulate as a result of dysregulated apoptosis and that these lymphocytes induce autoimmune destruction of myeloid and/or erythroid populations.
Research in our laboratory has focused on the inhibitors of apoptosis that might directly mediate survival of these cells and contribute to their resistance to Fas signaling. We have identified several survival pathways that are chronically active in patients with these diseases and contribute to accumulation of LGL cells. Signal transducers and activators of transcription (STAT) signaling has been found to regulate antiapoptotic survival in some tumors. STATs are transcription factors initially discovered as key signaling components that moderate responses to cytokine stimulation. We have data implicating STAT3 in the survival of NK- and T-LGLs. Mcl-1 is transcriptionally regulated by STAT3 and prevents apoptosis at the level downstream of Fas receptor signaling.
The mitogen-activated protein kinase (MAPK/ERK) pathway is another cascade that is important in LGL survival. We have found that MAPK/ERK was constitutively activated in 13 of 13 patients with NK-LGL leukemia and six of seven patients with T-LGL leukemia. The MAPK pathway coupled long-term survival of these LGL cells to constitutively activated Ras. These findings suggest that strategies to inhibit STAT or Ras/ERK/MAPK signaling pathways may be useful for the treatment of LGL leukemias.
I am also is interested in the mechanism of bone marrow failure in patients with LGL leukemia. A large number of NK receptors (killer cell immunoglobulin-like receptors, or KIRs) are expressed on NK cells and some T cells that recognize self-HLA alleles, thereby limiting the lysis of autologous cells. Ligands of the inhibitory KIRs are classic HLA Class I molecules, and engagement of these receptors inhibits the lytic activity of NK and T cells. Activating NK receptors are important in the recognition of tumor cells and virus-infected cells and mediate target cell lysis. We have found that the repertoire of NK receptors expressed on NK-LGL cells is skewed. Interestingly, patients with NK-LGL leukemia express a large number of activating KIRs (by genotype analysis) and lower levels of inhibitory KIR mRNA and protein than normal NK cells. Consistent with a high level of activating NK receptors, the NK-LGL cells have a potent cytolytic function. These results demonstrate that patients with NK-LGL leukemia have an increased activating-to-inhibitory KIR ratio. The major hypothesis guiding this research is that this altered ratio induces inappropriate lysis or cytokine production that has an impact on bone marrow production of erythroid and/or myeloid cells.