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Transcript of BCR-Abl
Breakpoint cluster region
Encodes the BCR protein
BCR normal function is unclear
Serine/threonine kinase activity
A GTPase-activating protein for RAC1 and CDC42
Conclusion/Future of the Gene
Encodes a cytoplasmic or nuclear protein tyrosine kinase
integrates signals from various Extracellular and intracellular sources and influences decision in regard to cell cycle and apoptosis
deletion of SH3 domain turns ABL into an oncogene => translocation => mutations in ABL activated
Chromosomal defect occurs when parts of Chromosome 9 and 22 swap places in a reciprocal translocation
head to tail fusion of BCR and ABL genes
elongated chromosome 9 and shorter chromosome 22 (oncogenic BCR-ABL gene fusion)
encodes for BCR-ABL fusion protein
molecular weight ranges from 185-210- kDa depending on precise location of breakage
Activity is negatively regulated by its SH3 domain
Deletion of the SH3 domain turns ABL1 into an oncogene
Regulation of cell growth and survival
Oxidative stress and DNA damage responses
BCR-ABL gene is a fusion of the BCR and ABL gene. This hybrid fuses through a process called Philadelphia translocation and creates the Bcr-Abl fusion gene. This mutant tyrosine kinase of the BCR-ABL gene codes for a protein that is "always on"; leading to unregulated cell division, among other things.
Development of the BCR-ABL fusion gene may lead to cancers such as Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML) and Chronic Neutrophilic Leukemia (CNL). CML is the most prevalent of these and accounts for 15-20% of all adult leukemias and 14% of all leukemias, affecting 6000 Americans per year. Therapy for these leukemias include tyrosine kinase inhibitors such as Imatinib (Glivec); however, resistance can be cultivated by the development of oncogene amplification and outside influences.
Types of Cancer
Therapies and Resistance
First generation drug
Second generation drugs
The creation and effects of Bcr-Abl
Abl1 gene on chromosome 9
BCR gene on chromosome 22
How Glivec works:
Prevents tyrosine-kinase enzyme (BCR-Abl) from phosphorylating subsequent proteins
Prevents initiating the signaling cascade necessary for cancer development
PTK activity is absolute requirement for malignant transformation
mutant tyrosine kinase of BCR-ABL gene codes for protein that is "always on" (unregulated cell division)
speed up cell division, inhibit DNA repair
increased proliferation, increased resistance to apoptosis, alteration of adhesion properties
different isoforms lead to different types of cancer
P190: acute lymphoblastic leukemia (ALL)
P210: chronic myeloid leukemia (CML)
P230: chronic neutrophilic leukemia
Tyrosine Kinase inhibitors
TKI blocks binding of ATP => phosphorylation prevented => BCR-ABL expressing cells either have selective growth disadvantage or undergo apoptosis cell death
Mutational frequencies appear to increase as disease (CML) progesses from chronic phase to blast phase
Forms of resistance:
Missense mutations within the ABL kinase domain
Over-expression of BCR-ABL
BCR-ABL gene is duplicated in DNA sequence
Increased production of transmembrane plasma proteins
Constitutive activation of downstream signaling molecules (ex: Src-family kinases)
developed to address imatinib intolerance and resistance
multi targeted inhibitor of Bcr-Abl family kinases
inhibits cells expressing a variety of mutations
effective against the T315I mutation
Which of the various signaling pathways activated by BCR-ABL such as Ras-MAP kinase, JAK-STAT and P13K-AKT is essential for the transformation?
What is the normal function of the BCR gene product?
Second-generation drugs offer improved potency and a greater likelihood of success in imatinib-resistant patients. There is also a growing interest in the idea that administration of multiple Abl kinase inhibitors in early phase patients could be used to delay or prevent the emergence of drug resistant clones.
Therefore, the combination of two agents targeting different pathways involved in cancer may significantly improve response rates and chances of survival.
In addition, if the signaling pathways with which the BCR-ABL gene uses to signal is discovered, scientists could have a new method of preventing the oncogenic abilities.