TY - JOUR
T1 - A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma
AU - Lin, Ying Wei
AU - Beharry, Zanna M.
AU - Hill, Elizabeth G.
AU - Song, Jin H.
AU - Wang, Wenxue
AU - Xia, Zuping
AU - Zhang, Zhenhua
AU - Aplan, Peter D.
AU - Aster, Jon C.
AU - Smith, Charles D.
AU - Kraft, Andrew S.
PY - 2010/1/28
Y1 - 2010/1/28
N2 - The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.
AB - The serine/threonine Pim kinases are upregulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre - T-LBL/T-ALL) being highly sensitive. Incubation of pre - T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phosphop70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogenactivated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre - T-LBL cells. In immunodeficient mice carrying subcutaneous pre - T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre - T-LBL.
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U2 - 10.1182/blood-2009-07-233445
DO - 10.1182/blood-2009-07-233445
M3 - Article
C2 - 19965690
AN - SCOPUS:77949319044
SN - 0006-4971
VL - 115
SP - 824
EP - 833
JO - Blood
JF - Blood
IS - 4
ER -