Structure and Function of Fusion Gene Products in Childhood...
Transcript of Structure and Function of Fusion Gene Products in Childhood...
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Structure and Function ofFusion Gene Products in
Childhood Acute Leukemia
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Chromosomal Translocations
Chr. 12
der(12)
Chr. 21
der(21)
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Distribution
A.T. Look, Science 278 (1997)
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Childhood ALL
• BCR-ABL t(9;22) 4%
Protein kinases
• TEL-AML1 t(12;21) 20%Transcription factors
• E2A-PBX1 t(1;19) 5%
• MLL fusions 6%MLL-AF4MLL-AF9MLL-ENL
t(4;11)t(1;11) t(11;19)
~ 30 diff. translocation partners
Transcription factor
Transcription factors
BCR-ABL p190 60%BCR-ABL p210 40%
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Transcriptional Activation
Sequence-specific DNA-binding factor
Co-Activator
Histon Acetylation Complex
DNA
Histone
Chromatin
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Transcriptional Activation
RNA Polymerase II
Gene Transcription
Histon Acetylation Complex
Chromatin Remodeling
Exposed site
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Transcriptional Repression
Co-Repressor
Histon Deacetylation Complex (HDAC)
Chromatin Condensation and Gene Silencing
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Combinatorial Control
Transcription factors build up
activating or repressing protein complexes
Differential effects depending
on molecular environment
Cross talk between
signaling pathways
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TEL
Synonym: ETV6
Ets-like transcription factor
Widely expressed in all normal tissues, frequently lost in tumors
Pointed ETSN- -C
DimerizationRecruiting Sin3A DNA-binding
Protein interaction
Central
Recruiting NCoR
Histone Deacetylation Complex Transcriptional repression,gene silencing
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AML1
Synonyms: RUNX1 / CBFA2 / PEB2αB
Gene family, homologous to Drosophila runt
RHDN- -CdimerizationDNA binding
transactivationTA
RHD TA
CBFß
Myb Ets C/EBP+
Co-activatorsCo-repressors
Gene transcription:e.g. Interleukin-3, GM-CSF, CSF1-R,TCRß, MyeloperoxidasePromotor
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TEL-AML1
TEL
PointedN- Central RHD -C
RHD TANcoR Myb Ets C/EBP+Enhanced Repression
Promotor
PNT
mSin3HDAC
Deregulation of AML1 target genes
CBFß
AML1
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Hematopoiesis
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TEL-AML1
J. Zhu et al., Oncogene 21 (2002)
– WT AML1:necessary for hematopoiestic stem cells
– TEL-AML1:generation of a pre-leukemic cellpopulation
– Secondary genetic lesions necessary for transformation
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E2A
– Regulator of lymphocyte differention
– bHLH transcription factorA
A
HLH
basic
Activation
DNA-binding – Regulates B-cell lineage genes,e.g. immunoglobulins,transcription factors EBF-1, Rag-1
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E2A-PBX1
HD
APBX
HD
AA
5‘-TGATTGAT-3‘
– homologous to Drosophila extradenticle (exd)
• PBX1
PBX
Mei
s
HDHD
A
5‘-TGATTGAT-3‘
– normally not expressed in lymphoid cells
Homeodomain
– Cofactor for HOX proteins
activation
• E2A-PBX1
– abberant Hox gene activation
repressionHox genes
activationHox genes
– Disturbance of lymphoid differentiation
– Promotion of uncontrolled cell division
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• MLL gene
MLL Fusions
P. Ernst et al., Curr. Oppin. Hematol. 9 (2002)
– homologous to Drosophila trithorax (trx)– Mixed Lineage Leukemia
• MLL fusions
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MLL Function– maintanance of Hox gene expression
– loss of MLL leads to severe developmental defects in mice
– Role in hematopoiesis: downstream or parallel of GATA-2
J. Zhu et al., Oncogene 21 (2002)
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Protein Kinases
• Phosphorylation of serine & threonine or tyrosine residues
• Phosphorylation is a common mechanism to regulate protein activity
• Protein phosphatases reverse the effects of protein kinases
– Tyrosine kinases
– Serine-threonine kinases
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• Receptor tyrosine kinases (membrane bound)
• Non-receptor tyrosine kinases (cytoplasmic)e.g. Src family of kinases
SH3 SH2 Protein kinaseYP
Bindsphosphotyrosine
Bindspolyprolinestretches
Phosphorylatedtyrosine
Inactivekinase
Tyrosine Kinases
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Signal transduction
S.G. Rane et al., Oncogene 21 (2002)
Cytokines(e.g. Interleukin, Interferon, CSFs, Erythropoietin)
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BCR-ABL• BCR
– Serine threonine kinase
• ABL– Tyrosine kinase, non-receptor type
– Distantly related to Src-kinases, ubiquitously expressed
– Oncogenic transformation requires deregulated tyrosine kinase activity
– Multifunctional kinase acting in different signaling pathways
– Role in cell cycle progression, activation of apoptosis
• BCR-ABL
– Causes enhanced proliferation and prolonged viability of cells
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BCR-ABL
B. Scheijen et al., Oncogene 21 (2002)
Not in p190BCR ABL
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Treatment Implications
• Gleevec™ / STI-571
– Successful in a murine model of ALL
– Almost no side effects
– Successful in treatment of CML
– Occurrence of resistancy in acute leukemia
– Tyrosine kinase inhibitor, selective for Abl, c-Kit and PDGFR
• Ras pathway inhibitor
– Investigated in clinical trials