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
 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

Sawyers. N Engl J Med. 1999;340:1330.

Faderl et al. Ann Intern Med. 1999;131:207.
 The Ph Chromosome and the bcr-abl
Gene: The t(9;22) Translocation*
Chromosome 9 q+

Chromosome 9

Philadelphia Chromosome
(or 22q-)

Chromosome 22

bcr-abl

bcr
FUSION PROTEIN WITH CONSTITUTIVE
TYROSINE KINASE ACTIVITY
abl

Melo. Blood. 1996;88:2375.

Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643.
 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 Substrate
activates a substrate
protein, eg, PI3
kinase, by Effector
phosphorylation Bcr-Abl
• This activated
substrate initiates a P
ADP
signaling cascade
culminating in cell PPP
ATP
proliferation and
survival PPP
SIGNALING
ADP = adenosine diphosphate; ATP = adenosine triphosphate;
P = phosphate.
Savage and Antman. N Engl J Med. 2002;346:683
Scheijen and Griffin. Oncogene. 2002;21:3314.
 Imatinib Mesylate:
Mechanism of Action*
• Imatinib mesylate
occupies the ATP
binding pocket of
the Abl kinase Bcr-Abl
domain
• This prevents
substrate P
phosphorylation ATP
and signaling PPP
Imatinib
• A lack of signaling mesylate SIGNALING
inhibits proliferation
and survival
Savage and Antman. N Engl J Med. 2002;346:683.
 Imatinib Mesylate in Chronic Phase CML
Following IFN- Failure: Overall Survival*

1.0
0.9
Survival probability

0.8
0.7
0.6
0.5
0.4
Total Dead
0.3
261 31 Imatinib mesylate
0.2 251 193 Others
0.1 (P<0.0001)
0
0 24 48 72 96
Months
Kantarjian et al. Blood. 2004;104;1979. Copyright American Society of Hematology, used with permission.
 Case Study: WBC
Probably not really linear
90000
Begins Imatinib Treatment
80000

70000
No. Leucocytes

60000

50000

40000

30000

20000

10000

0
2/13/04

4/13/04

6/13/04

8/13/04

2/13/05

4/13/05

6/13/05

8/13/05
10/13/04

12/13/04

10/13/05
Date

White Blood Count progression in subject beginning

one year before being diagnosed, and continuing
throughout the first year of treatment with STI-571.
 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”