Constitutively activated FLT3 phosphorylates BAD partially through Pim-1

Kyu Tae Kim, Mark Levis, Donald Small

Research output: Contribution to journalArticle

Abstract

Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukaemogenesis and their presence is associated with a poor prognosis in acute myeloid leukaemia (AML). Examining the anti- and proapoptotic proteins in constitutively activated FLT3 signalling in BaF3/ITD and MV4-11 cells, we found that the level of Bcl-2 antagonist of cell death (BAD) phosphorylation was greatly decreased in response to FLT3 inhibition. Both Ser-112 and Ser-136 of BAD are rapidly dephosphorylated after treatment with the FLT3 inhibitor CEP-701 in BaF3/ITD and MV4-11 cells. In confirmation of the cell line data, BAD was highly phosphorylated in both constitutively activated wild-type and mutant FLT3 primary AML samples, and rapidly dephosphorylated after treatment of the primary samples with CEP-701. Upstream proteins known to phosphorylate BAD include Akt, extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAPK), Pim-1 and Pim-2. We and other groups have shown that constitutively activated FLT3 induces multiple signalling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, Erk/MAPK and Janus kinase/signal transducers and activators of transcription (Jak/STAT). Thus, BAD may be a nexus point upon which these multiple signalling pathways converge in FLT3-mediated cell survival. In support of this, siRNA knockdown of BAD expression in MV4-11 cells conferred resistance to CEP-701-mediated apoptosis. Our data suggests that Pim-1 is one of the principal kinases mediating the anti-apoptotic function of FLT3/ITD signalling via the phosphorylation of BAD.

Original languageEnglish (US)
Pages (from-to)500-509
Number of pages10
JournalBritish journal of haematology
Volume134
Issue number5
DOIs
StatePublished - Sep 1 2006

Keywords

  • BAD
  • CEP-701
  • FLT3
  • FLT3/ITD
  • Pim-1

ASJC Scopus subject areas

  • Hematology

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