Molecular Medicine Dr Catherine Flynn Consultant Haematologist St James’s Hospital October 22 nd...
Transcript of Molecular Medicine Dr Catherine Flynn Consultant Haematologist St James’s Hospital October 22 nd...
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Molecular Medicine
Dr Catherine Flynn
Consultant Haematologist
St James’s Hospital
October 22nd 2009
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Molecules
DNA mRNA ProteinTranscription Translation
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Cell CycleStem Cells/ Quiescence
Do different cancer stem cells have the same Achilles' heel ???
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Molecules… at the bench…..
DNA mRNA ProteinTranscription Translation
Micro array
SNP
Proteomics
Short Inhibitory RNA
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………….To The Bedside• What is the biology of acute myeloid
leukaemia?
• What is the best treatment for chronic myeloid leukaemia?
• Which Patient should have a transplant?
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Haematopoiesis
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Morphology
Karyotype
Molecular Diagnostics
Leukaemia Diagnosis
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• Modify Diagnosis
• Counsel patient and family better re prognosis
• Recommend specific treatment
DNA mRNA Protein
Symptoms and Signs Laboratory Findings
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Haematopoiesis
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Leukaemia
• An Acquired Cancer– (rare inherited leukaemias reported)
Differentiation Arrest
Mutations disrupt genes controlling Proliferation
uncontrolled growth of an immature clone of cells
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Hematology 2007;2007:509-520
Model of leukaemogenesis with two cooperating classes of mutations
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Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Structure of a Human Chromosome
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Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Chromosomal Abnormalities in Human Cancer
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Acute Myeloid Leukaemia
Abnormalities seen in at least 50 %of cases
Karyotype is of major prognostic significance
Used in planning treatment
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Acute Myeloid Leukaemia
Favourable Intermediate Poor
t(8;21) AML1/ETO
Normal Karyotype
Complex karyotype ( >3)
inv(16) inv(3) or t(3;3)
t(15;17)
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Survival from CR by MRC Cytogenetic Risk Group
100
75
50
25
0
FavourableIntermediate Poor
0 1 2 3 4 5
Years from randomisation
68%
44%
18%2P <0.00001
% s
till
ali
ve
Similar results in SWOG/EGOG study (Slovak et al, 2000 ) and CALGB (Byrd et al, 2002)
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Karyotypic Normal AML
• "Should I recommend an allogeneic stem-cell transplant, or not?"
Graft versus Leukaemia/ Potential Cure
Toxicity/Mortality
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Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2007;2007:7-00028
Figure 2. Cells with multiple Auer rods (arrow) may be appreciated
Acute Promyelocytic Leukaemia (APML)
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Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Lazarchick, J. ASH Image Bank 2009;2009:8-00163
Figure 1. A "faggot" cell present on the peripheral smear from a patient with acute promelocytic leukemia is shown
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Myeloid Maturation
Differentiation Arrest in APML
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Licht J. N Engl J Med 2009;360:928-930
Countering PML/RARα with All-trans Retinoic Acid
RARα
PML
Encourages Self Renewal
Blocks differentiation
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The karyotype of patients with Acute Myeloid Leukaemia can be helpful. PML/RARα translocation is found in AML called acute promyelocytic leukaemia (APML). This fusion
protein……….
is re
spons
ible
for t
he...
is c
ause
d by
a tra
nsl...
is a
ssoci
ated
with
a ..
.
pre
dicts
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of onse
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is o
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een in
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eld.
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20% 20% 20%20%20%A. is responsible for the
response to Retinoic Acid/ATRA
B. is caused by a translocation between chromosomes 15 and 19
C. is associated with a poor outcome
D. predicts age of onsetE. is only seen in the elderly
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Chronic Myeloid Leukaemia
A Paradigm for Malignancy
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2 3 4 51
7 8 9 10
11 126
13 14 15 16 17 18
The Philadelphia Chromosome
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Philadephia Chromosome
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The Ideal Target for Molecular Therapy
Present in the majority of patients with the disease
Determined to be the causative abnormality
Has unique activity that is
- Required for disease induction
- Dispensable for normal cellular function
Courtesy of BJ Druker, MD
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Bcr-Abl as a Therapeutic Target for CML
Bcr-Abl is detected in 95% of patients with CML
Bcr-Abl is the causative abnormality of CML
Bcr-Abl tyrosine kinase is constitutively activated
intracellularly
Tyrosine kinase activity is required for CML cell
function
Abl null mice are viable
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(From Novartis Pharma)
(C(C3030HH3535NN77SOSO44))
NN
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HH
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Imatinib mesylateImatinib mesylate (STI571 - Glivec(STI571 - Glivec®®))
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Goldman J and Melo J. N Engl J Med 2001;344:1084-1086
Mechanism of Action of STI571/Glevec/Imatinib
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Goldman, J. M. et al. N Engl J Med 2003;349:1451-1464
Signal-Transduction Pathways Affected by BCR-ABL
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Druker B et al. N Engl J Med 2006;355:2408-2417
Kaplan-Meier Estimates of the Cumulative Best Response to Initial Imatinib Therapy
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Chronic Myeloid Leukaemia
Janet Rowley Receives Presdential Medal of Freedom August 2009
Chronic Myeloid Leukaemia
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STI 571/Gleevec/Imatinib was developed in the late 1990s to treat CML.
Its mode of action is in ………
DNA m
ethyl
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hib...
Pro
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Inhi
bition
of c
ell d
iffer
...
20% 20% 20%20%20%A. DNA methylation
B. Cell cycle arrest
C. Tyrosine kinase inhibitor
D. Protein destruction
E. Inhibition of cell differentiation
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