genetic mutations that lead to chronic myelogenous leukemia: causes and treatments marty o’neill...
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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”