Elevated Fas Ligand and BA21 Serorecognition as Disease Correlates in Bone Marrow Failure Disorders: Taking Advantage of the LGL Leukemia Model.

Persistently expanded large granular lymphocytes (LGL) are found in bone marrow failure disorders such as pure red cell aplasia, myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and in LGL leukemia. Many of the characteristics of BMF diseases overlap and it is postulated they share a fundamental pathogenetic link. LGL leukemia represents the best characterized disease of LGL, and was used as a model to study pathogenic LGL proliferation in bone marrow failure diseases. LGL leukemia cells are characteristically resistant to Fas-regulated death, despite expressing high levels of Fas receptor and Fas ligand (FasL). Elevated FasL may cause the neutropenia that is observed in many LGL leukemia patients. A poorly understood feature of LGL leukemia is serorecognition of a discreet epitope derived from the HTLV envelope BA21 region. To query the common pathogenesis in all of the BMF disorders, FasL expression and BA21 seroreactivity levels were obtained for patients with bone marrow failure disease (n=87). The serum FasL levels as determined by antigen capture were inversely correlated with neutrophil counts regardless of disease subtype. A positive correlation was noted between FasL expression and lymphocytosis, basophile counts, and serum chloride mEgL (Pearson correlation p values 0.0621, 0.0224, 0.0465). Negative correlations for FasL included neutrophil count and serum albumin levels (p= 0.0333 and 0.0657 respectively). Initial data from an assay we designed to obtain standardized anti-BA21 IgG data revealed a strong negative correlation for BA21 IgG and FasL (−0.3668) for the PNH cohort. An additional moderately positive Pearson correlation for FasL and BA21 IgG was found only for the LGL leukemia group (0.1813), although all BMF groups demonstrated elevated IgG recognition of BA21 (n=78). In addition, FasL and BA21 IgG levels were most elevated in female patients. Our results suggest that FasL and BA21 IgG levels correlate with certain laboratory features of hematopoeitic inhibition as well as with patient gender. A potential utility in discriminating between bone marrow failure disease subtypes and determining treatment response potentials could also be realized with further study.