Transcript Intoduction to Leukemia Slides

Products of haematopoiesis
Leukaemia, the current
hypothesis
• Defect in maturation of white blood cells-may
involve a block in differentiation and/or a block in
apoptosis
• Transformation events-Acquired genetic defect
• Initiating events unclear
• Chromosomal translocation implicated in many
forms of leukaemia
Leukaemia Incidence
ALL
11%
others
17%
CML
15%
CLL
26%
CLL - Chronic Lymphocytic
ALL - Acute Lymphocytic
AML
31%
CML - Chronic Mylogenous
AML - Acute Mylogenous
bcr-abl Gene and Fusion Protein Tyrosine Kinases
9+
9
Philadelphia
chromosome
22
bcr
t(9;22) Translocation
bcr-abl
fusion gene
abl
Chromosome 9
Chromosome 22
bcr
1
13
14
ALL
CML
breakpoint breakpoint
c-abl
1
2-11
p190 bcr-abl
ALL
p210 bcr-abl
CML
Targeted Therapy
• Imatinib Mesylate
– Binds BCR-ABL kinase domain - -P
– Frontline therapy for CML since 2001
• Second generation Kinase inhibitors
– Dasatinib (Sprycel)
– Nilotinib (Tasigna)
• Model for rational drug design
MLL
• Implicated in infant, childhood and adult
leukaemia
• Implicated in myeloid , lymphoid and
mixed lineage leukaemias
• 11q23 abnormalities (38 different
translocations)
• t(4;11), t(9;11)
• Poor prognosis
AML1
•
•
•
•
•
21q
AML1-ETO t(8;21)
t(3;21)
TEL-AML t(12;21)
Loss of trans-activation domain critical to
t(8;21) and t(3;21) abnormalities
• Inv (16)
Molecular Mechanisms of AML1
action
ALL-Primary cytogenetic subgroups
Cytogenetics
Molecular
FAB/ Incidence
Clinical
t(4,11)
MLL/AF-4
L1, L2
>90% infantile ALL
Often congenital, very high WBC
worst prognosis
t(9,22)
BCR-ABL (p190)
L1, L2
5% paediatric ALL
25% adult ALL
Very high WBC count,
expression of myeloid Antigens.
TK activity v elevated
t(1,19)
ELA/PBX
L1, L2
5-6% of ALL
High WBC count, high serum
LDH, low event-free survival
t(12,21)
TEL/AML1
L1, L2
30% childhood ALL
25% ALL
Childhood disease (2-10yrs),
High cure rate with standard
chemotherapy
t(8,14)
MYC/IgH
L3
3% ALL
Older children/young adults,
high risk
>50
chromosomes
FISH for trisomy 21
L1, L2
Lower WBC count & serum
LDH, age 2-10
Summary
• Molecular changes implicated in development of
leukaemia
• Translocation is a major mechanism
• CML - a paradigm for malignancy
• Mutations in master genes such as AML1 and
MLL disrupt control of haematopoiesis leading to
development of leukaemia
• Knowledge of molecular changes can influence
diagnosis, prognosis and treatment
Further Reading
•
Chronic myeloid leukemia--advances in biology and new approaches to treatment.
Goldman JM, Melo JV
New England Journal of medicine 2003;349:1451-64
•
Molecular characterization of acute myeloid leukemia and its impact on
treatment
Olga Frankfurt, Jonathan D. Licht and Martin S. Tallman
Current Opinion in Oncology 2007;19:635-649
•
Molecular Genetics of Acute Lymphoblastic Leukemia
Scott A. Armstrong and A. Thomas Look
Journal of Clinical Oncology 2005;23:6306-6315