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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4192-4199
TRANSPLANTATION
Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents
graft-versus-host disease but spares the graft-versus-leukemia function
of the bone marrow allografts in a murine bone marrow
transplantation model
Fatih M. Uckun,
Bertram A. Roers,
Barbara Waurzyniak,
Xing-Ping Liu, and
Marina Cetkovic-Cvrlje
From the Experimental BMT Program, Parker Hughes Cancer
Center and Departments of Immunology, Pathology, Chemistry, and Drug
Discovery Program, Parker Hughes Institute, St Paul, MN.
The purpose of the present study was to evaluate the effects of
graft-versus-host disease (GVHD) prophylaxis with the Janus kinase 3 (JAK3) inhibitor WHI-P131/JANEX-1 on the graft-versus-leukemic (GVL)
function of marrow allografts in mice undergoing bone marrow transplantation (BMT) after being challenged with an otherwise invariably fatal dose of BCL-1 leukemia cells. GVHD prophylaxis using
WHI-P131 markedly improved the survival outcome after BMT. The
probability of survival at 30 days after BMT was 11% ± 6% for
vehicle-treated recipients (median survival time, 25 days) versus
63% ± 12% for recipients treated with WHI-P131 (median survival
time, 36 days; P < .0001). Because WHI-P131 is devoid of
antileukemic activity against BCL-1 leukemia cells, this marked improvement in survival outcome was due to reduced incidence of GVHD-associated fatalities combined with sustained GVL function of the
allografts in the WHI-P131 group. Notably, adoptive transfer experiments demonstrated that the spleens of WHI-P131-treated allograft recipients contained less than 0.001% BCL-1 cells. Notably, GVHD prophylaxis with WHI-P131 plus methotrexate resulted in 100% survival of mice receiving allotransplants challenged with an otherwise
invariably fatal dose of BCL-1 leukemia. Taken together, our results
provide strong experimental evidence that GVHD prophylaxis using
WHI-P131 does not impair the GVL function of the allografts and
consequently contributes to an improved post-BMT survival outcome of
the recipient mice.
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