Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL–positive leukemias identified by a proteomics approach

Balabanov, Stefan; Gontarewicz, Artur; Ziegler, Patrick; Hartmann, Ulrike; Kammer, Winfried; Copland, Mhairi; Brassat, Ute; Priemer, Martin; Hauber, Ilona; Wilhelm, Thomas; Schwarz, Gerold; Kanz, Lothar; Bokemeyer, Carsten; Hauber, Joachim; Holyoake, Tessa L.; Nordheim, Alfred; Brümmendorf, Tim H.

doi:10.1182/blood-2005-03-037648

Cited by 89 publications

(72 citation statements)

References 53 publications

(47 reference statements)

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“…After 48 hours of treatment, the viable cells were assayed for their ability to transform 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) into purple formazan, as described previously. 23 The compound concentration that inhibits response by 50% (IC 50 ) is defined as the concentration resulting in 50% growth inhibition that corresponds to the fraction affected (F a value) of 0.5. All tested cells were exposed to 10 different concentrations of each compound.…”

Section: Mtt Assaymentioning

confidence: 99%

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Gontarewicz

Balabanov

Keller

et al. 2008

Blood

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157

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The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically ex-

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Section: Mtt Assaymentioning

confidence: 99%

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Gontarewicz

Balabanov

Keller

et al. 2008

Blood

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157

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“…25 In addition, overexpression of Eif5a was of interest, as this is the only eukaryotic protein known to be activated by post-translational hypusination, and hypusination inhibitors have demonstrated an antiproliferative effect on leukemic cell lines in vitro. 26 Several other genes, including Dtx1, Iltifb, Igh, were found to be overexpressed in both the SCL/LMO1 and LMO1 only tumors. Although we had predicted that the SCL/LMO1 and LMO1 only tumors would be fairly similar, the list of commonly overexpressed genes was relatively small.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets

Lin

Aplan

2007

Leukemia

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We compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice that overexpressed SCL, LMO1 or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38, were consistently more than fourfold overexpressed in pre-T LBL from all three genotypes analyzed, and a single gene, Prss16 was consistently underexpressed. However, we identified a number of genes, such as Cfl1, Tcra, Tcrb, Pbx3, Eif4a, Eif4b and Cox8b that were over or under-expressed in pre-T LBL that arose in specific transgenic lines. Similar to the situation seen with human pre-T LBL, the SCL/LMO1 leukemias displayed an expression profile consistent with mature, late cortical thymocytes, whereas the NHD13 leukemias displayed an expression profile more consistent with immature thymocytes. We evaluated two of the most differentially regulated genes as potential therapeutic targets. Cfl1 was specifically overexpressed in SCL-LMO1 tumors; inactivation of Cfl1 using okadaic acid resulted in suppression of leukemic cell growth. Overexpression of Ccl8 was a consistent finding in all three transgenic lines, and an antagonist for the Ccl8 receptor-induced death of leukemic cell lines, suggesting a novel therapeutic approach.

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“…These effects could be achieved using concentrations of drugs which did not significantly impair proliferation of CD34þ selected cells from healthy donors. It was also seen that transfected cells which over expressed eIF-5A were relatively protected from the effects of the drug combination [82].…”

Section: The Role Of the Proteasomementioning

confidence: 97%

Therapeutic targets in chronic myeloid leukaemia

Heaney

Holyoake

2007

Hematological Oncology

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Chronic myeloid leukaemia (CML) is a clonal disorder of the haemopoietic stem cell arising as a consequence of the formation of the bcr-abl oncogene. The particular molecular basis of this condition has enabled the development of therapies that selectively target diseased cells. The success of the rationally designed first-line therapy imatinib mesylate (IM) is tempered by the problems of disease persistence and resistance. Novel strategies have been identified to take forward therapy in CML and these will be discussed in this review. This work is generated from a review of published literature and contains particular insight into the work performed by our group in this field.

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Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL–positive leukemias identified by a proteomics approach

Abstract: Inhibition of BCR-ABL

Cited by 89 publications

References 53 publications

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets

Therapeutic targets in chronic myeloid leukaemia

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