Yoko Nakano

Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway.

The WT1 gene is overexpressed in human primary leukemia and a wide variety of solid cancers. The WT1 gene is alternatively spliced at two sites, yielding four isoforms: 17AA(+)KTS(+), 17AA(+)KTS(−), 17AA(−)KTS(+), and 17AA(−)KTS(−). Here, we showed that 17AA(+)WT1-specific siRNA induced apoptosis in three WT1-expressing leukemia cell lines (K562, HL-60, and Kasumi-1), but not in WT1-non-expressing lymphoma cell line (Daudi). 17AA(+)WT1-specific siRNA activated caspase-3 and -9 in the intrinsic apoptosis pathway but not caspase-8 in the extrinsic one. On the other hand, 17AA(−)WT1-specific siRNA did not induce apoptosis in the three WT1-expressing cell lines. The apoptosis was associated with activation of proapoptotic Bax, which was activated upstream of the mitochondria. Constitutive expression of 17AA(+)WT1 isoforms inhibited apoptosis of K562 leukemia cells induced by apoptosis-inducing agents, etoposide and doxorubicin, through the protection of mitochondrial membrane damages, and DNA-binding zinc-finger region of 17AA(+)WT1 isoform was essential for the antiapoptotic functions. We further studied the gene(s) whose expression was altered by the expression of 17AA(+)WT1 isoforms and showed that the expression of proapoptotic Bak was decreased by the expression of 17AA(+)KTS(−)WT1 isoform. Taken together, these results indicated that 17AA(+)WT1 isoforms played antiapoptotic roles at some points upstream of the mitochondria in the intrinsic apoptosis pathway.

Hematological aspects of a novel 9-aminoanthracycline, amrubicin.

Our previous study showed that the myelosuppression induced by a single‐bolus intravenous injection of amrubicin into mice was more severe, even at half the maximum tolerated dose (MTD), than that induced by adriamycin (ADR) at the MTD, but that the recovery was more rapid than that after ADR. The present study shows that the administration of amrubicin significantly decreased the number of colony‐forming units of granulocytes and monocytes (CFU‐GM) from day 1, but that the CFU‐GM numbers recovered by day 3. In contrast, the administration of ADR induced a continuous decrease in the numbers of CFU‐GM until day 10. The early myelosuppression and rapid recovery of white blood cells (WBC) induced by amrubicin may depend upon the early decrease in the number of CFU‐GM and the rapid recovery of CFU‐GM. These data suggest that the toxic effects on the peripheral blood and bone marrow induced by amrubicin are more reversible and more controllable than those induced by ADR.