Genetic Mutations that Lead to

Chronic Myelogenous Leukemia:Causes and Treatments

Marty O’Neill II

Carmen Banea

What is CML?

• Chronic Myelogenous Leukemia (CML) is defined as, “a malignant cancer of the bone marrow. It causes rapid growth of the blood-forming cells (known as myeloid precursors) in the bone marrow, peripheral blood, and body tissues.” [2]

• CML represents about 14% of all occurrences of leukemias.

• Patients who have CML are said to be in one of the following three phases (in order of occurrence): • the chronic phase (between 1 and 15% blasts) • the accelerated phase (between 15% - 30% blasts)• the blast phase (more than 30% blasts). [5]

Symptoms and Diagnosis

• CML can be discovered in a routine physical examination

• 70% of those diagnosed with CML had symptoms including: fatigue, abdominal discomfort, weight loss, and sweating

• Philadelphia Chromosome is indicator that patient has CML

Sawyers. N Engl J Med. 1999;340:1330. Faderl et al. Ann Intern Med. 1999;131:207.

Epidemiology of CML*

• Median age range at presentation is 45-55 years

• Incidence increases with age– Up to 30% of patients are aged >60 years

• 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

Melo. Blood. 1996;88:2375. Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643.

The Ph Chromosome and the bcr-abl Gene: The t(9;22) Translocation*

FUSION PROTEIN WITH CONSTITUTIVE

TYROSINE KINASE ACTIVITY

bcr-abl

bcr

Philadelphia Chromosome (or 22q-)

Chromosome 9 q+

abl

Chromosome 9

Chromosome 22

Genetic Mutations

• Can occur as exposures to radiation, chemicals, etc

• Known from 1981 or before that Benzene (a byproduct of the use of laser printers and copy machines) caused the mutation leading to CML in humans

• Not enough has been done to protect employees who work in the presence of Benzene

Treatments

• Transplantation is the only known cure.

• Chemo Therapy

• Imatinib (STI-571)

• BMS-354825 and AMN107 (still under study)

Normal Bcr-Abl Signaling*

• The kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation

• This activated substrate initiates a signaling cascade culminating in cell proliferation and survival

PP P

ADP P

P

PP P

ATP

SIGNALING

Bcr-Abl

Substrate

Effector

ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.Savage and Antman. N Engl J Med. 2002;346:683Scheijen and Griffin. Oncogene. 2002;21:3314.

Imatinib Mesylate: Mechanism of Action*

• Imatinib mesylate occupies the ATP binding pocket of the Abl kinase domain

• This prevents substrate phosphorylation and signaling

• A lack of signaling inhibits proliferation and survival

P

PP P

ATP

SIGNALING

Imatinib mesylate

Bcr-Abl

Savage and Antman. N Engl J Med. 2002;346:683.

Imatinib Mesylate in Chronic Phase CML Following IFN- Failure: Overall Survival*

Kantarjian et al. Blood. 2004;104;1979. Copyright American Society of Hematology, used with permission.

0 24 48 72 96

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Su

rviv

al p

rob

abili

ty

Total Dead

261 31

251 193

Imatinib mesylate

Others

(P<0.0001)

Case Study: WBC

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

2/13

/04

4/13

/04

6/13

/04

8/13

/04

10/1

3/04

12/1

3/04

2/13

/05

4/13

/05

6/13

/05

8/13

/05

10/1

3/05

Date

No

. L

euco

cyte

s

White Blood Count progression in subject beginning one year before being diagnosed, and continuing throughout the first year of treatment with STI-571.

Probably not really linear

Begins Imatinib Treatment

Case Study: Probable Cause of CML

• Worked in a Copy Center for five years directly before diagnosis

• Probable cause of genetic mutations that led to CML was exposure to benzene

• Nothing has been done to further examine or address this problem in that copy center

From: http://www.seton.com/

Conclusions

• CML research has been ongoing for over 150 years

• Better methods of treatment have been found that targets the CML cells on a molecular level

• The causes of CML are still not completely known, but benzene has been known for at least 25 years to lead to CML

• New regulations and education programs are needed to protect employees who work in the presence of benzene

References• [1] D’Antonio, J. Chronic Myelogenous Leukemia. Clinical Journal of Oncology Nursing.

9(5): 535-8.

• [2] Faderl et al. Oncology (Huntingt). 1999; 13:169.

• [3] Genetic Science Learning Center at the University of Utah. http://gslc.genetics.utah.edu/.

• [4] National Marrow Donor Program overview slide presentation. http://www.marrow.org/NMDP/SLIDESET/sld031.htm.

• [5] Medline Plus Medical Encyclopedia. http://nlm.nih.gov.

• [6] Pasternak et al. Chronic Meylogenous Leukemia: Molecular and Cellular Aspects. J Cancer Res Clin Oncol. 1998; 643-60.

• [7] Rinsky et al. Leukemia in Benzene Workers. Am J Ind Med. 1981; 2(3): 217-45.

• [8] Smith, MT & Zhang, L. Biomarkers of Leukemia Risk: Benzene as a Model. Environ Health Perspect. 1998 Aug; 106 Suppl 4:937-46.

• [9] STI-571 in Chronic Myelogenous Leukaemia. British Journal of Haematology. 2002; 15-24.

* Some slides in this presentation were borrowed or adapted from IMPACT “The Era of Molecular Therapy: Focus on Chronic Myelogenous Leukemia”