Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation

Amy D. Hartman, Annique Wilson-Weekes, Attaya Suvannasankha, Gem S. Burgess, Carissa A. Phillips, Katie J. Hincher, Larry Cripe, H. Boswell

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Abstract

Objective: c-jun N-terminal kinase (JNK) has been implicated in proliferation and survival downstream from the tyrosine kinase oncogene, p210 BCR-ABL, in chronic myeloid leukemia. We studied whether a similar relationship between JNK and FMS-like tyrosine kinase 3 (Flt3) describes acute myeloid leukemia (AML). Methods: By immunoprecipitation, Flt3 was found to be activated and identified as the potential origin of JNK activity in a heavy majority of JNK+ve AML blasts tested. Often, Flt3 activity is associated with activating mutation of the gene locus. However, statistical linkage tied JNK activity with Flt3 expression levels rather than with mutation. An adaptor network to describe the signal cascade Flt3-to-JNK was uncovered. Results: Active Flt3 was linked to p85 phosphoinositide-3 (PI-3) kinase, and p85 with cbl and CrkII/CrkL by co-immunoprecipitaton assays from lysates of model cell lines and primary AML blasts. JNK1 co-immunoprecipitated from such lysates with p85-cbl-crkII/L and bound to Crk species SH3 domain in pull-down assay. siRNA-mediated depletion of Flt3 or of cbl, the adaptor at the nexus of this signaling group, inhibited JNK activity on substrate c-jun. Within AML blast cells influenced by Flt3 signaling, selective inhibition of JNK by a small molecule inhibitor, led to proliferative inhibition, apoptosis, and sensitizing cells to the anthracycline, daunorubicin. These effects occurred upon JNK inhibition without off-target inhibition of extracellular signal-regulated kinase or AKT pathways, and p38-kinase activation, an effector in the p53/p14 arf tumor suppressor pathway, was also maintained or augmented. Conclusion: JNK is a bonafide signaling pathway from Flt3 in AML whose function for proliferation and survival is required in a significant AML cohort with active Flt3 signaling, by mutation or overexpression of Flt3.

Original languageEnglish
Pages (from-to)1360-1376
Number of pages17
JournalExperimental Hematology
Volume34
Issue number10
DOIs
StatePublished - Oct 2006

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JNK Mitogen-Activated Protein Kinases
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Phosphotransferases
Mutation
Daunorubicin
1-Phosphatidylinositol 4-Kinase
src Homology Domains
MAP Kinase Signaling System
Anthracyclines
Extracellular Signal-Regulated MAP Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Oncogenes
Immunoprecipitation
Small Interfering RNA
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation. / Hartman, Amy D.; Wilson-Weekes, Annique; Suvannasankha, Attaya; Burgess, Gem S.; Phillips, Carissa A.; Hincher, Katie J.; Cripe, Larry; Boswell, H.

In: Experimental Hematology, Vol. 34, No. 10, 10.2006, p. 1360-1376.

Research output: Contribution to journalArticle

Hartman, Amy D. ; Wilson-Weekes, Annique ; Suvannasankha, Attaya ; Burgess, Gem S. ; Phillips, Carissa A. ; Hincher, Katie J. ; Cripe, Larry ; Boswell, H. / Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation. In: Experimental Hematology. 2006 ; Vol. 34, No. 10. pp. 1360-1376.
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abstract = "Objective: c-jun N-terminal kinase (JNK) has been implicated in proliferation and survival downstream from the tyrosine kinase oncogene, p210 BCR-ABL, in chronic myeloid leukemia. We studied whether a similar relationship between JNK and FMS-like tyrosine kinase 3 (Flt3) describes acute myeloid leukemia (AML). Methods: By immunoprecipitation, Flt3 was found to be activated and identified as the potential origin of JNK activity in a heavy majority of JNK+ve AML blasts tested. Often, Flt3 activity is associated with activating mutation of the gene locus. However, statistical linkage tied JNK activity with Flt3 expression levels rather than with mutation. An adaptor network to describe the signal cascade Flt3-to-JNK was uncovered. Results: Active Flt3 was linked to p85 phosphoinositide-3 (PI-3) kinase, and p85 with cbl and CrkII/CrkL by co-immunoprecipitaton assays from lysates of model cell lines and primary AML blasts. JNK1 co-immunoprecipitated from such lysates with p85-cbl-crkII/L and bound to Crk species SH3 domain in pull-down assay. siRNA-mediated depletion of Flt3 or of cbl, the adaptor at the nexus of this signaling group, inhibited JNK activity on substrate c-jun. Within AML blast cells influenced by Flt3 signaling, selective inhibition of JNK by a small molecule inhibitor, led to proliferative inhibition, apoptosis, and sensitizing cells to the anthracycline, daunorubicin. These effects occurred upon JNK inhibition without off-target inhibition of extracellular signal-regulated kinase or AKT pathways, and p38-kinase activation, an effector in the p53/p14 arf tumor suppressor pathway, was also maintained or augmented. Conclusion: JNK is a bonafide signaling pathway from Flt3 in AML whose function for proliferation and survival is required in a significant AML cohort with active Flt3 signaling, by mutation or overexpression of Flt3.",
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T1 - Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation

AU - Hartman, Amy D.

AU - Wilson-Weekes, Annique

AU - Suvannasankha, Attaya

AU - Burgess, Gem S.

AU - Phillips, Carissa A.

AU - Hincher, Katie J.

AU - Cripe, Larry

AU - Boswell, H.

PY - 2006/10

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