Transcript Here are some CML slides that may be helpful for your

Here are some CML slides that
may be helpful for your
presentation.
Chronic Myeloid Leukemia (CML)
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Accounts for 15-20% of adult leukemias
Median age is 50-60 years
Higher incidence noted in patients with heavy radiation
exposure
In 1960, Nowell and Hungerford detected the
Philadelphia chromosome (22q-).
In 1973, Rowley identified the reciprocal translocation
involving chromosome 9 : t(9;22)(q34;q11).
In 1980s, the unique fusion gene termed BCR-ABL was
discovered.
Epidemiology of CML
Median age range at presentation: 45 to 55 years
Incidence increases with age
Up to 30% of patients are >60 years old
Slightly higher incidence in males
Male-to-female ratio—1.3:1
At presentation
50% diagnosed by routine laboratory tests
85% diagnosed during chronic phase
Sawyers CL. N Engl J Med. 1999;340:1330-1340.
Faderl S, et al. Ann Intern Med. 1999;131:207-219.
CML: Peripheral Blood Smear
Normal
Chronic phase CML
Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.
Pathogenesis of CML
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A single, pleuripotential, hematopoietic stem cell
acquires a Ph chromosome carrying the BCL-ABL fusion
gene  proliferative advantage
 Constitutive expression by leukemic stem cell of growth
factors ( Il-3, G-CSF)
 CML cells survive longer due to defective apoptosis
 Close proximity of the BCR and ABL genes in
hematopoietic cells in interphase may favor translocations.
 Transformation from the chronic phase to blast phase is
associated with additional molecular changes ( activation of
oncogenes or deletion of tumor-suppressor genes)
Pathogenesis of CML
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The classic BCR-ABL gene result from the fusion of
parts of two normal genes  ABL on Ch9 and BCR on
Ch22.
 Both genes are ubiquitously expressed in normal
tissue,but their precise functions are not well defined.
 Break occurs in ABL upstream of exon a2 and the
major breakpoint cluster region of the BCR gene 
a 5’ portion of BCR and a 3’ portion of ABL are
juxtaposed on a shortened Ch22.
 The mRNA molecules transcribed from this hybrid
gene contain one of two BCR-ABL junctions: e13a2
and e14a2  translated into p210BCR-ABL
Pathogenesis of CML
What causes the leukemogenic potential of p210bcr-abl?
The constitutive activation of the ABL tyrosine
kinase activity by BCR
 deregulated cellular proliferation
 decreased adherence of leukemic cell to the stroma
 reduced apoptotic response to mutagenetic stimuli
 Most crucial domain : the tyrosine kinase encoded by
the SRC-homology 1 (SH1) domain on ABL
 Various substrates have been found to bind to BCRABL and to be tyrosine –phosphorylated by it.
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The Translocation of t(9;22)(q34;q11) in CML
Faderl, S. et al. N Engl J Med 1999;341:164-172
Molecular Targets
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Target for inhibition: Tyrosine kinase
 Aim: to design a small chemical compound that would
compete with ATP for its binding site in the kinase
domain.
 By blocking the ATP site, no phosphate groups would
be transferred to tyrosine residues on the BCR-ABL
substrate  unphosphorylated substrate protein would
not be able to undergo a conformational change to
allow it to associate with downstream effectors  the
downstream reactions would then be impeded 
interrupting transmission of the oncogenic signal to
the nucleus.
Molecular Targets
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Imatinib Mesylate (Gleevec, STI571): a small molecule
that inhibits the kinase activity of all proteins that
contain ABL, ABL-related gene protein, PDGFR, as
well as c-kit receptor.
It was first approved in 2001.
It occupies the ATP binding site in the SH1 domain of
the BCR-ABL oncoprotein.
It inhibits cellular growth and induces apoptosis.
Other targeted therapies being investigated:
The more specific Tyrosine Kinase inhibitors such as
the dual SRC-ABL inhibitor : Dasatanib
which was approved in June by the FDA.
Translocation Leading to the Philadelphia (Ph) Chromosome and the Role of BCR-ABL in th
Pathogenesis of CML (Panel A) and the Effect of Normal (Panel B) and Abnormal (Panel C) cFunction on Platelet-Derived Growth Factor and Gastrointestinal Stromal Tumors
Savage, D. G. et al. N Engl J Med 2002;346:683-693
Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib
Savage, D. G. et al. N Engl J Med 2002;346:683-693
Clinical Course: Phases of Untreated CML
Chronic phase
Median duration
5–6 years
Advanced phases
Accelerated
phase
Blast crisis
Median duration
6–9 months
Median survival
3–6 months
p53, Rb, p16, t(3;21),
t(8;21), t(7;11)
Faderl S, et al. Ann Intern Med. 1999;131:207-219.
Pasternak G, et al. J Cancer Res Clin Oncol. 1998;124:643-660.