normal haemopoiesis
DESCRIPTION
Normal haemopoiesis. ABNORMALITIES IN THE HEMOPOIETIC SYSTEM. CAN LEAD TO HEMOGLOBINOPATHIES HEMOPHILIA DEFECTS IN HEMOSTASIS/THROMBOSIS HEMATOLOGICAL MALIGNANCY. MUTATIONS AND DNA. VARIOUS TYPES OF MUTATIONS CAN OCCUR LEADING TO DISEASE PHENOTYPE POINT MUTATIONS INSERTIONS OR DELETIONS - PowerPoint PPT PresentationTRANSCRIPT
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Normal haemopoiesis
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ABNORMALITIES IN THE HEMOPOIETIC SYSTEM
• CAN LEAD TO
• HEMOGLOBINOPATHIES
• HEMOPHILIA
• DEFECTS IN HEMOSTASIS/THROMBOSIS
• HEMATOLOGICAL MALIGNANCY
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MUTATIONS AND DNA
• VARIOUS TYPES OF MUTATIONS CAN OCCUR LEADING TO DISEASE PHENOTYPE
• POINT MUTATIONS• INSERTIONS OR DELETIONS• TRANSLOCATIONS• COMPLEX CHROMOSOMAL
REARRANGEMENTS
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EXAMPLE OF COMMON MUTATIONS IN HUMAN DISEASE
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Sickle cell disease
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Sickle cell disease, morphology and molecular
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VARIABILITY IN GENETIC DISEASES
•ONE DISEASE, ONE GENE, ONE MUTATION
•ONE DISEASE, ONE GENE, MANY MUTATIONS
•ONE DISEASE, MORE THAN ONE GENE, MANY •MUTATIONS
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HAEMOPHILIA
X LINKED RECESSIVE DISORDER
HAEMOPHILIA A – MUTATIONS IN FACTOR VIII GENE
HAEMOPHILIA B – MUTATIONS IN FACTOR IX GENE
SIMPLE AND COMPLICATED MUTATIONS
THE FLIP TIP MUTATION
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F8A
E1 E22 E23 E26
F8A
E1 E22 E23 E26
TEL CEN
CEN
CENTEL
TEL
INVERSION 22
E1E22 E23 E26
A
B
C
FIGURE 4 THE IVS 22 MUTATION IN HAEMOPHILIA A.
F8B
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Genetic factors and deep vein thrombosis
• FACTOR V LEIDEN MUTATION• PROTHROMBIN MUTATION• ? OTHER FACTORS IN THE PROTEIN C
PATHWAY• FVL LEADS TO SIGNIFICANT INCREASE IN
RISK OF DVT, PARTICULARLY IN ASSOCIATION WITH OTHER ENVIRONMENTAL FACTORS EG OCP
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CANCER DEVELOPMENT: ITS IN THE GENES
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HOW DOES A CELL BECOME TUMORIGENIC?
• THREE PROCESSES ARE INVOLVED
• IMMORTALISATION
• TRANSFORMATION
• METASTASIS
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IMMORTALISATION
• PROCESS BY WHICH THE CELLS ARE INDUCED TO GROW INDEFINITELY
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TRANSFORMATION
• CELLS ARE NOT CONSTRAINED IN TERMS OF GROWTH CHARACTERISTICS AND TEND TO BECOME FACTOR INDEPENDENT
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METASTASIS
• CANCER CELLS GAIN THE ABILITY TO INVADE NORMAL TISSUE AND ESTABLISH OTHER FOCI OF MALIGNANCY
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WHAT CAUSES CELL TRANSFORMATION?
• ENVIRONMENTAL• CARCINOGENS(INITIATORS AND
PROMOTERS)
• GENETIC• SOMATIC MUTATIONS• MENDELIAN INHERITANCE
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ONCOGENES• NORMAL CELLULAR
COUNTERPARTS(PROTO-ONCOGENES)
• MUTATION/ACTIVATION LEADS TO TUMOR FORMATION
• HUNDREDS OF ONCOGENES IDENTIFIED
• GAIN OF FUNCTION
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Tumour suppressor genes
• Originally known as recessive oncogenes
• Need to have both copies of the gene affected to promote a malignant phenotype
• Knudsons 2 hit hypothesis
• First mutation makes cells susceptiple to development of cancer
• 2nd hit leads to a malignant phenotype
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TRANSLOCATIONS AND CANCER
• SEEMS PARTICULARLY RELEVANT IN HEMATOLOGICAL MALIGNANCIES
• CHRONIC MYELOID LEUKEMIA
• ACUTE PROMYELOCYTIC LEUKEMIA
• BURKITTS LYMPHOMA
• NON HODGKINS LYMPHOMA
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Leukaemia, the current hypothesis
• Defect in maturation of white blood cells• May involve a block in differentiation and/or a
block in apoptosis• Acquired genetic defect• Initiating events unclear• Transformation events involve acquired genetic
changes• Chromosomal translocation implicated in many
forms of leukaemia
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Chronic Myeloid Leukaemia• Malignancy of the haemopoietic system• Transformation of the pluripotent stem cell• 9;22 translocation giving rise to the Philadelphia
(Ph’) chromosome• Creation of a leukaemia specific mRNA (BCR-
ABL)• Resistance to apoptosis, abnormal signalling and
adhesion• Molecular diagnostics• Molecular and cellular therapeutics
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Cytogenetic Abnormality of CML:The Ph Chromosome
1 2 3 4 5
6 7 8 10 119 12
13 14 15 16 17 18
19 20 21 22 x Y
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The Ph Chromosome: t(9;22) Translocation
22
bcr
abl
Ph ( or 22q-)
bcr-abl
FUSION PROTEINWITH TYROSINEKINASE ACTIVITY
9 9 q+
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Prevalence of the Ph Chromosome in Haematological Malignancies
Leukaemia % of Ph+ Patients
CML 95
ALL (Adult) 15–30
ALL (Paediatric) 5
AML 2
Faderl S et al. Oncology (Huntingt). 1999;13:169-184.
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bcr-abl Gene and Fusion Protein Tyrosine Kinases
Adapted from Melo JV. Blood. 1996;88:2375-2384.
p210Bcr-Abl
p185Bcr-Abl2-11
2-11
Chromosome 9
c-bcr
Chromosome 22
c-abl
Exons
Introns
CML Breakpoints
ALL Breakpoints
1
2-11
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NON HODGKINS LYMPHOMA
• B CELL FOLLICULAR LYMPHOMA
• t(14;18)(q21;q14)
• BCL 2 AND IMMUNOGLOBULIN GENES INVOLVED
• DYSREGULATION OF BCL 2
• FAILURE OF APOPTOSIS
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Detecting Cancer – where to begin?
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Detecting cancer, the need for a marker of disease
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Detecting Cancer – different markers for different diseases?
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Cancer Molecular Diagnostics – discriminating cancers at the gene level
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How Cancer Molecular Diagnostics?
• Chromosome analysis
• Gene analysis
• Gene expression analysis
• Protein analysis
• Gene chip analysis
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Leukaemia diagnostics
• Morphology
• Cytogenetics
• Fluorescent In Situ Hybridisation (FISH)
• Immunophenotyping
• PCR of chromosomal translocations
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New developments in Cancer Molecular DiagnosticsThe Gene Chip
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The Gene Chip, a Molecular snap shot of the cell
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MOLECULAR MEDICINE
• A new approach to medicine
• New Diagnostics
• New Therapeutics
• A number of agents now in clinical trials
• Molecular medicine will help identify new targets and permit rational drug development