Abstract
Monosomy 7 and interstitial deletions in the long arm of chromosome 7 (-7/7q-) is a chromosomal abnormality found in 10 to 30% of myeloid disorders including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). -7/7q- is more frequently found in radiation- or chemotherapy-related AML/MDS, whose prognosis is known to be poor. Using an array CGH technology, we identified three candidate myeloid tumor suppressors (Samd9=Kasumi, Samd9L=Titan, LOC253012=Miki) from a common microdeletion cluster in 7q21.3 subband. Among them, Kasumi and Titan locate adjacent each other and share a common gene structure with 60% amino acid identity, while mouse has Titan gene alone. Because Titan-deficient mice develop AML at a high frequency, deletion of Kasumi and/or Titan is predisposal to human AML/MDS. Titan protein possibly participates in the degradation of endocytosed cytokine receptors; In Titan-downregulated cells, cytokine receptors were accumulated in intracellular vesicles, where sustained activation of cytokine signaling was seen after cytokine stimulation. Another candidate -7/7q- responsible gene, Miki, locates to mitotic spindles and centrosomes. Miki protein would contribute to the maturation of centrosomes toward mitosis because it was found that downregulation of Miki by RNA interference caused smaller mitotic centrosomes and induced abnormalities in mitosis and nuclear morphology, similar to myelodysplasia. We are now focusing on the isolation of genetical or epi-genetical gene alterations that occurs collaboratively with -7/7q- and are studying to elucidate the molecular mechanism of -7/7q- AML/MDS. This would lead us to the development of -7/7q- targeted drugs.
