MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundLarge granular lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies. Design and MethodsTo investigate a non-mendelian genetic predisposition to large granular lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified 'random forests' technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays. ResultsOur analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on large granular lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with large granular lymphocyte leukemia than in matched controls (64% versus 41%, P<0.001, homozygous 40% versus 15%, P<0.001). Flow cytometry was employed to determine the expression of MICA within hematologic compartments, showing that the signal intensity of MICA was increased in granulocytes from neutropenic patients with large granular lymphocyte leukemia in comparison with that in controls (P=0.033). Furthermore, neutrophil counts were inversely correlated with MICA expression (R 2 =0.50, P=0.035). Finally, large granular lymphocyte leukemia cells were able to selectively kill MICA + Ba/F3 lymphocytes transfected with human MICA*019 in a dose-dependent manner compared to naïve cells (P<0.001), an effect mitigated by administration of an anti-NKG2D antibody (P=0.033). ConclusionsOur results illustrate that MICA-NKG2D played a role in disease pathogenesis in the majority of patients in our cohort of cases of large granular lymphocyte leukemia and further investigation into this signaling axis may provide potent therapeutic targets. Haematologica 2010;95(10): 1713-1721. doi:10.3324/haematol.2010 MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia © F e r r a t a S t o r t i F o u n d a t i o n

Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation

“…3 In a transplantation setting, MICA polymorphisms may influence alloreactivity of immune effector cells bearing the cognate receptor, leading to differences in relapse control. [25][26][27] In particular, the MICA-129 dimorphism (met/val) has been associated with differential binding affinity toward the NKG2D receptor. 28 It has been shown that this, in turn, leads to differences in downstream phosphorylation of SRC kinases.…”

MICA (MHC class I polypeptide-related sequence A)

“…MICA is also expressed in abundance in large granular lymphocyte leukemia cells. Neutrophil counts were inversely correlated with MICA expression and MICA*00801/A5.1 was reported in higher frequency in patients with large granular lymphocyte leukemia (Viny et al, 2010).…”

Large granular lymphocytic leukaemia pathogenesis and management

“…This is a non-peptide presenting stress-induced major histo-compatability (MHC)-like molecule which is the cognate receptor for NKG2D which is abundant on LGLs. Thus, the interaction between MICA and NKG2D may play a role in disease pathogenesis (Viny et al, 2010). Another candidate gene in the pathogenesis of both T-and NK-LGL leukaemias is TSC-22, a transforming growth factor b-inducible gene.…”