Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype

Neben, Kai; Schnittger, Susanne; Brors, Benedikt; Tews, Björn; Kokocinski, Felix; Haferlach, Torsten; Müller, Jasmin; Hahn, Meinhard; Hiddemann, Wolfgang; Eils, Roland; Lichter, Peter; Schoch, Claudia

doi:10.1038/sj.onc.1208344

Cited by 63 publications

(54 citation statements)

References 43 publications

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“…Myt-1 became phosphorylated and thereby inactivated by PKC412 in the former, whereas it became dephosphorylated and thereby activated in the latter, leading to the increased phosphorylation of CDC2. It is of note that Wee1, another kinase involved in tyrosine-15 phosphorylation, was below the detection limit in FLT3 mutation-positive leukemic cells as previously described (Neben et al, 2005).…”

Section: Flt3 Mutation-dependent Responses To Pkc412mentioning

confidence: 50%

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G 2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G 2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutationdependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia.

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Section: Flt3 Mutation-dependent Responses To Pkc412mentioning

confidence: 50%

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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“…29,30). HOXB5 up-regulation has also been implicated in leukemia (31), and high expression levels of HOXB5 are associated with poor outcome (32). The Pim-1 serine/ threonine kinase was highly up-regulated in NUP98-HOXA9-expressing cells.…”

Section: Resultsmentioning

confidence: 84%

Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation

Chung¹,

Morrone

Schuringa

et al. 2006

Cancer Research

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The t(7;11)(p15;p15) translocation, observed in acute myelogenous leukemia and myelodysplastic syndrome, generates a chimeric gene where the 5 ¶ portion of the sequence encoding the human nucleoporin NUP98 protein is fused to the 3 ¶ region of HOXA9. Here, we show that retroviral-mediated enforced expression of the NUP98-HOXA9 fusion protein in cord bloodderived CD34 + cells confers a proliferative advantage in both cytokine-stimulated suspension cultures and stromal coculture. This advantage is reflected in the selective expansion of hematopoietic stem cells as measured in vitro by cobblestone area-forming cell assays and in vivo by competitive repopulation of nonobese diabetic/severe combined immunodeficient mice. NUP98-HOXA9 expression inhibited erythroid progenitor differentiation and delayed neutrophil maturation in transduced progenitors but strongly enhanced their serial replating efficiency. Analysis of the transcriptosome of transduced cells revealed up-regulation of several homeobox genes of the A and B cluster as well as of Meis1 and Pim-1 and down-modulation of globin genes and of CAAT/enhancer binding protein A. The latter gene, when coexpressed with NUP98-HOXA9, reversed the enhanced proliferation of transduced CD34 + cells. Unlike HOXA9, the NUP98-HOXA9 fusion was protected from ubiquitination mediated by Cullin-4A and subsequent proteasome-dependent degradation. The resulting protein stabilization may contribute to the leukemogenic activity of the fusion protein. (Cancer Res 2006; 66(24): 11781-91)

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“…This did not apply to NRAS mutations and NRAS wild-type samples, suggesting that only FLT3-LM and FLT3-TKD are associated with a specific signature (Neben et al, 2005). In a similar approach, Lacayo et al (2004) were able to identify cases with FLT3-LM, FLT3-TKD, and those without either mutation in a series of 81 childhood AML, although there were significant overlaps between the respective groups (Lacayo et al, 2004).…”

Section: Molecular Genetics In Amlmentioning

confidence: 68%

“…In a series of 110 AML patients with normal karyotype, Neben et al (2005) were able to separate samples with FLT3-LM and FLT3-TKD, with up to 100% accuracy. This did not apply to NRAS mutations and NRAS wild-type samples, suggesting that only FLT3-LM and FLT3-TKD are associated with a specific signature (Neben et al, 2005).…”

Section: Molecular Genetics In Amlmentioning

confidence: 99%

Gene expression profiling for the diagnosis of acute leukaemia

et al. 2006

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An optimised diagnostic setting in acute leukaemias combines cytomorphology and cytochemistry, multiparameter immunophenotyping, cytogenetics, fluorescence in situ hybridisation, and polymerase chain reaction (PCR)-based assays. This allows classification and definition of biologically defined and prognostically relevant subtypes, and allows directed treatment in some subentities. Over the last years the microarray technology has helped to quantify simultaneously the expression status of ten thousands of genes in single experiments. This novel approach will hopefully become an essential tool for the molecular classification of acute leukaemias in the near future. It can be anticipated that new biologically defined and clinically relevant subtypes of leukaemia will be identified based on their unique gene expression profiles. This method may therefore guide therapeutic decisions and should be investigated in a diagnostic setting in parallel to established standard methods.

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Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype

Cited by 63 publications

References 43 publications

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation

Gene expression profiling for the diagnosis of acute leukaemia

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