Abstract
The Bcr-Abl translocation t(9;22)(q34;q11 ) defines a subgroup of ALL patients with a dismal prognosis despite the introduction of intensified induction and consolidation regimen. Although Bcr-Abl induced NF-kappaB/Rel activation has previously been shown, the role of NF-kappaB/Rel in Ph+ leukemia is unclear. Using DNA binding assays, we demonstrate constitutive NF-kappaB/Rel activity in nuclear extracts from Ph+ ALL blasts, whereas Ph- primary blast cells and B-precursor cell lines lack NF-kappaB/Rel activity. NF-kappaB/Rel activity was shown in the ela2 and the b2a2 subtypes. Constitutive NF-kappaB/Rel activity in Ph+ blasts is not due to elevated endogenous IkappaB kinase (IKK) activity as shown by immune complex kinase assays. Since NF-kappaB/Rel is a transcriptional regulator of inhibitors of apoptosis we examined the expression of anti-apoptotic genes known to be induced by NF-kappaB/Rel by real time PCR analysis. We found no induction of TRAFI, TRAF2, cIAPI, cIAP2, XIAP, A20 or Bfl/Al in Ph+ ALL samples as compared to Ph-negative ALL controls. In summary, constitutive NF-kappaB/Rel activation independent of endogenous IKK activation may be a common finding in Ph+ ALL. However, targets of NF-kappaB/Rel mediated transcriptional regulation in this disease remain to be identified.
Publication types
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Multicenter Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Forkhead Transcription Factors
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Fusion Proteins, bcr-abl / physiology
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Gene Expression Regulation, Neoplastic
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Humans
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I-kappa B Kinase
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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NF-kappa B / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins
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Oncogene Proteins v-rel / metabolism*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor alpha-Induced Protein 3
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X-Linked Inhibitor of Apoptosis Protein
Substances
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DNA-Binding Proteins
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FOXG1 protein, human
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Forkhead Transcription Factors
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nerve Tissue Proteins
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Nuclear Proteins
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Oncogene Proteins v-rel
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Proteins
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RNA, Messenger
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RNA, Neoplasm
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Fusion Proteins, bcr-abl
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3