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 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4150-4157.
Prepublished online as a Blood First Edition Paper on September 4, 2009; DOI 10.1182/blood-2009-03-212852.

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LYMPHOID NEOPLASIA

Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells

Lisa S. Chen1, Sanjeev Redkar2, David Bearss2, William G. Wierda3, and Varsha Gandhi1,3

1 Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston; 2 SuperGen Inc, Dublin, CA; and 3 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston

Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction.


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