Genetic Variation in AKAP13 Is Associated with Increased Risk of Relapse after Allogeneic Hematopoietic Cell Transplantation Following Non-Myeloablative Conditioning.

With the introduction of non-myeoloablative conditioning, allogeneic hematopoietic cell transplants (HCT) have become an attractive treatment option for patients who due to age or comorbidities are ineligible for myeloablative conditioning transplants. Although mortality related to the toxicity of the conditioning regimen is reduced, relapse is still a considerable problem. Several polymorphisms giving rise to minor histocompatibility antigens (mHag) have been claimed to reduce relapse of the malignant disease, by increasing the GVT effect. The A-kinase anchor protein 13 (AKAP13 or HA-3) has previously been identified as the source protein of such a mHag, and isoforms of the protein are implicated in both hematological and non-hematological malignancies. AKAP13 activates Rho GTPases, which mediate cellular processes such as cell growth and transcriptional activation, and show an enhanced activity in human cancers. To assess the influence of polymorphism in the AKAP13 gene on the outcome of allogeneic HCT following non-myeloablative conditioning, 124 consecutive patient-donor pairs receiving allogeneic HCT with matched related (n=77) or unrelated (n=47) donors for hematological malignancies (Hodgkin’s disease, N=14; multiple myeloma, N=15; chronic lymphocytic leukaemia, N=16; non-Hodgkin’s lymphoma, N=26; myelodysplastic syndrome, N=24, acute myeloid leukaemia, N=27; chronic myeloid leukaemia, N=2), between March 2000 and November 2006 at Rigshospitalet, Denmark, were genotyped for 9 different single nucleotide polymorphisms (SNPs) in AKAP13. Three SNPs with frequencies of the minor allele > 1% were chosen for further analysis (rs2061821, rs2061822, rs2061824). The 3 SNPs displayed strong pair-wise linkage disequilibrium (D′ = 1) segregating into 4 different inferred haplotypes. HCT outcome was analyzed according to the 4 haplotypes (11 patients were excluded from further analysis due to failed genotyping). The frequencies of haplotypes 1 to 4 in patients were 60.0 %, 35.9%, 3.6% and 0.5%, respectively. In a cox regressional model only homozygosity for haplotype 1 conferred a significantly increased risk of mortality (hazard ratio 2.2; 95% CI 1.2–4.1). Since overall survival (OS) was similar in patients carrying any combination of haplotypes 2 to 4, these were pooled and considered as one group in the following analyses. 32% of the patients were homozygous for haplotype 1 while 68% carried any combination of haplotype 2–4. The median followup was 751 days (range 38–2904 days). Compared to patients with any combination of haplotype 2–4, the patients homozygous for haplotype 1 had a significantly decreased OS (18% vs. 61%, p=0.01) and increased relapse related mortality (59% vs. 17%, p=0.005) There were no significant differences in progression free survival, acute and chronic graft versus host disease when analysed according to haplotype. No association was found between outcome and recipient / donor mismatches of the 3 SNPs, which potentially could encode mHag’s, arguing that the reduced OS in patients homozygous for haplotype 1 is not caused by reduced GVT effect. Collectively, our data suggest, that homozygosity for the AKAP13 haplotype 1 confers a significantly higher risk of mortality after nonmyeloablative conditioning allogeneic HCT, due to mortality related to the relapse or progression of the malignant disease. The 3 SNPs are located in close proximity to an auto-inhibitory site in the N-terminal region of the protein, hereby possibly disrupting its activity and constitutively increasing the activity of the Rho GTPases.