Molecular Medicine Dr Catherine Flynn Consultant Haematologist St James’s Hospital October 22 nd 2009
Molecular Medicine
Dr Catherine Flynn
Consultant Haematologist
St James’s Hospital
October 22nd 2009
Molecules
DNA mRNA ProteinTranscription Translation
Cell CycleStem Cells/ Quiescence
Do different cancer stem cells have the same Achilles' heel ???
Molecules… at the bench…..
DNA mRNA ProteinTranscription Translation
Micro array
SNP
Proteomics
Short Inhibitory RNA
………….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?
Haematopoiesis
Morphology
Karyotype
Molecular Diagnostics
Leukaemia Diagnosis
• Modify Diagnosis
• Counsel patient and family better re prognosis
• Recommend specific treatment
DNA mRNA Protein
Symptoms and Signs Laboratory Findings
Haematopoiesis
Leukaemia
• An Acquired Cancer– (rare inherited leukaemias reported)
Differentiation Arrest
Mutations disrupt genes controlling Proliferation
uncontrolled growth of an immature clone of cells
Hematology 2007;2007:509-520
Model of leukaemogenesis with two cooperating classes of mutations
Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Structure of a Human Chromosome
Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Chromosomal Abnormalities in Human Cancer
Acute Myeloid Leukaemia
Abnormalities seen in at least 50 %of cases
Karyotype is of major prognostic significance
Used in planning treatment
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)
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)
Karyotypic Normal AML
• "Should I recommend an allogeneic stem-cell transplant, or not?"
Graft versus Leukaemia/ Potential Cure
Toxicity/Mortality
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)
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
Myeloid Maturation
Differentiation Arrest in APML
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
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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t
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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
Chronic Myeloid Leukaemia
A Paradigm for Malignancy
2 3 4 51
7 8 9 10
11 126
13 14 15 16 17 18
The Philadelphia Chromosome
Philadephia Chromosome
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
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
(From Novartis Pharma)
(C(C3030HH3535NN77SOSO44))
NN
NN
NN
HH
NN
HH
NNNN
NN
OO
NN
Imatinib mesylateImatinib mesylate (STI571 - Glivec(STI571 - Glivec®®))
Goldman J and Melo J. N Engl J Med 2001;344:1084-1086
Mechanism of Action of STI571/Glevec/Imatinib
Goldman, J. M. et al. N Engl J Med 2003;349:1451-1464
Signal-Transduction Pathways Affected by BCR-ABL
Druker B et al. N Engl J Med 2006;355:2408-2417
Kaplan-Meier Estimates of the Cumulative Best Response to Initial Imatinib Therapy
Chronic Myeloid Leukaemia
Janet Rowley Receives Presdential Medal of Freedom August 2009
Chronic Myeloid Leukaemia
STI 571/Gleevec/Imatinib was developed in the late 1990s to treat CML.
Its mode of action is in ………
DNA m
ethyl
atio
n
Cel
l cyc
le a
rres
t
Tyr
osine
kinas
e in
hib...
Pro
tein
des
truct
ion
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