Here are some CML slides that may be helpful for your

presentation.

Chronic Myeloid Leukemia (CML)Chronic Myeloid Leukemia (CML) 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.

Sawyers CL. N Engl J Med. 1999;340:1330-1340. Faderl S, et al. Ann Intern Med. 1999;131:207-219.

Median age range at presentation: 45 to 55 yearsIncidence increases with age

Up to 30% of patients are >60 years oldSlightly higher incidence in males

Male-to-female ratio—1.3:1At presentation

50% diagnosed by routine laboratory tests85% diagnosed during chronic phase

Epidemiology of CML

Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.

Normal Chronic phase CML

CML: Peripheral Blood Smear

Pathogenesis of CMLPathogenesis of CML 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 CMLPathogenesis of CML 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 CMLPathogenesis 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 BCR-

ABL and to be tyrosine –phosphorylated by it.

Faderl, S. et al. N Engl J Med 1999;341:164-172

The Translocation of t(9;22)(q34;q11) in CML

Molecular TargetsMolecular Targets 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 TargetsMolecular Targets 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.

Savage, D. G. et al. N Engl J Med 2002;346:683-693

Translocation Leading to the Philadelphia (Ph) Chromosome and the Role of BCR-ABL in the Pathogenesis of CML (Panel A) and the Effect of Normal (Panel B) and Abnormal (Panel C) c-kit

Function 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

Chronic phase

Median duration5–6 years

Accelerated phase

Median duration6–9 months

Blast crisis

Median survival3–6 months

Advanced phases

Faderl S, et al. Ann Intern Med. 1999;131:207-219.Pasternak G, et al. J Cancer Res Clin Oncol. 1998;124:643-660.

Clinical Course: Phases of Untreated CML

p53, Rb, p16, t(3;21), t(8;21), t(7;11)