Studies are proposed on a recently identified, novel human kinase. The observations that it is mitogen-activated and nuclear-localized suggest it is a prime candidate to regulate transcription factors. Its activity is markedly and constitutively elevated in the peripheral blood lymphocytes of patients with acute leukemia. Purification and microsequencing indicate it is homologous to a Drosophila developmental regulator, fsh, known to activate the transcription factor, trithorax, and to a human gene of unknown function, RING3. Preliminary data reveal that RING3 interacts with ALL1, a human homolog of trithorax that has been linked to 11q23 acute leukemias. RING3 transforms NIH/3T3 cells, rendering them tumorigenic in nude mice, and can be activated by Ras and BCR-ABL. The applicant proposes to determine: (1) if RING3 phosphorylates and activates ALL-1; (2) how BCR-ABL and Ras activate RING3 kinase; (3) whether RING3 expression causes leukemia in transgenic mice and (4) the extent of the correlation between RING3 kinase activity and leukemia. The central hypothesis to be tested is that RING3 kinase is part of a signal transduction pathway that includes ALL-1 and is deregulated in leukemia.
