Transcript Haematopoiesis

Molecular Medicine
October 22nd 2009
Dr Catherine Flynn
Consultant Haematologist
St James’s Hospital
Molecules
Transcription
DNA
Translation
mRNA
Protein
Cell Cycle
Stem Cells/
Quiescence
Do different cancer stem cells have the
same Achilles' heel ???
Molecules… at the bench…..
Transcription
DNA
SNP
Translation
Protein
mRNA
Short Inhibitory RNA
Micro array
Proteomics
………….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
Leukaemia Diagnosis
Morphology
Karyotype
Molecular
Diagnostics
Symptoms and Signs
DNA
mRNA
Laboratory Findings
Protein
• Modify Diagnosis
• Counsel patient and family better re
prognosis
• Recommend specific treatment
Haematopoiesis
Leukaemia
• An Acquired Cancer
– (rare inherited leukaemias reported)
Differentiation
Arrest
Mutations
disrupt genes
controlling
Proliferation
uncontrolled growth of an immature clone of cells
Model of leukaemogenesis with two
cooperating classes of mutations
Hematology 2007;2007:509-520
Risk
Factors?
Structure of a Human Chromosome
Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Chromosomal Abnormalities in Human Cancer
Frohling S and Dohner H. N Engl J Med 2008;359:722-734
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
inv(16)
Normal
Karyotype
Complex
karyotype ( >3)
inv(3) or t(3;3)
t(15;17)
Survival from CR by MRC Cytogenetic
Risk Group
Favourable
Intermediate
Poor
% still alive
100
75
68%
50
44%
25
18%
2P <0.00001
0
0
1
2
3
4
5
Years from randomisation
Similar results in SWOG/EGOG study (Slovak et al, 2000 ) and CALGB (Byrd et al, 2002)
Karyotypic Normal AML
• "Should I recommend an allogeneic stemcell transplant, or not?"
Graft versus
Leukaemia/
Potential
Cure
Toxicity/Mortality
Acute Promyelocytic Leukaemia
(APML)
Figure 2. Cells with multiple Auer rods (arrow) may be appreciated
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2007;2007:7-00028
Figure 1. A "faggot" cell present on the peripheral smear from a patient with acute
promelocytic leukemia is shown
Lazarchick, J. ASH Image Bank 2009;2009:8-00163
Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Myeloid Maturation
Differentiation
Arrest in APML
Countering PML/RARα with All-trans Retinoic Acid
Blocks
differentiation
RARα
PML
Encourages Self
Renewal
Licht J. N Engl J Med 2009;360:928-930
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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……….
A. is responsible for the
20% 20% 20% 20% 20%
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 onset
E. is only seen in the elderly
Chronic Myeloid Leukaemia
A Paradigm for Malignancy
The Philadelphia Chromosome
1
2
3
6
7
8
13
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15
9
4
5
1
0
11
12
16
17
18
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
Imatinib mesylate (STI571 - Glivec®)
(C30H35N7SO4)
H
N
N
N
H
N
N
N
N
O
N
(From Novartis Pharma)
Mechanism of Action of STI571/Glevec/Imatinib
Goldman J and Melo J. N Engl J Med 2001;344:1084-1086
Signal-Transduction Pathways Affected by BCR-ABL
Goldman, J. M. et al. N Engl J Med 2003;349:1451-1464
Kaplan-Meier Estimates of the Cumulative Best Response to
Initial Imatinib Therapy
Druker B et al. N Engl J Med 2006;355:2408-2417
Chronic Myeloid Leukaemia
Chronic Myeloid Leukaemia
Janet Rowley Receives Presdential
Medal of Freedom August 2009
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STI 571/Gleevec/Imatinib was developed in
the late 1990s to treat CML.
Its mode of action is in ………
A. DNA methylation
20% 20% 20% 20% 20%
B. Cell cycle arrest
C. Tyrosine kinase
inhibitor
D. Protein
destruction
E. Inhibition of cell
differentiation