JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.

Therapy-related myelodysplasia (MDS) is a fatal marrow disorder distinct from primary MDS. We examined the efficacy of bone marrow transplantation (BMT) as a treatment for patients with therapy-related MDS. Eighteen patients with therapy-related MDS and twenty-five patients with primary MDS received an allogeneic, syngeneic, or unrelated donor BMT. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, FK-506, or T cell depletion. Conditioning regimens consisted of cyclophosphamide/total body irradiation, with and without cytosine arabinoside, busulfan/cyclophosphamide, and cyclophosphamide/etoposide/carmustine. For patients with therapy-related MDS, the median age was 32 years and the actuarial disease-free survival was 24% (95% confidence interval 6, 42%) with a median follow-up of 3 years. For patients with primary MDS, the median age was 36 years and the actuarial disease-free survival at 3 years was 43% (95% confidence interval 22, 64%). Four of the therapy-related patients and two of the primary patients have relapsed. Three patients experienced graft failure; all three had received T cell-depleted marrow and two had marrow fibrosis. Our results suggest that patients with therapy-related MDS can be successfully transplanted. Transplantation should be considered early in the disease, since long-term disease-free survival is achievable.