Genetic Mutations that Lead to Chronic Myelogenous Leukemia:

1
Genetic Mutations that Lead to Chronic
Myelogenous Leukemia Causes and Treatments
Marty ONeill II Carmen Banea martyoneillii_at_gmai
l.com, carmen.banea_at_gmail.com University of North
Texas
Introduction
Discussion
Causes
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), and the blast phase (more than 30
blasts). 5 The chronic phase is the initial
phase and the phase in which patients are most
often diagnosed with CML 1. The accelerated and
blast phases are subsequent phases that represent
further progression of CML in the patient and
decreased chances of survival after
treatment. Research concerning CML started in
the XIX Century and is still in progress. There
have been many important discoveries concerning
CML regarding its causes, methods of detection in
patients, treatments, and possible
vaccines. Knowledge of Chronic Myelogenous
Leukemia can be dated back to the mid-1800s when
symptoms of CML were first documented by Velpeau.
Research continued, and about 20 years later, a
high concentration of white blood cells in
patients with CML was discovered. The term
myelogenous was coined by Neuman after his 1878
discovery that bone marrow may not be the only
place where blood cells were formed. In 1960,
two scientists who lived in Philadelphia,
Pennsylvania discovered what would later be
called the Philadelphia (Ph) Chromosome a direct
indication of CML. The Philadelphia
Chromosome results from a reciprocal
translocation of parts of chromosomes 9 and 22 as
is shown in Figure 1. This results in a shortened
chromosome 22 called the Philadelphia
Chromosome.
Genetic mutations occur due to DNA damage caused
by external agents such as ultraviolet light,
nuclear radiation, or certain chemicals. 3
Mutations may also occur during the process of
copying DNA in preparation for cell division.
Even such common occurrences as exposure to
benzene (produced by photocopy machines), in
concentrations not greatly above the current
legal standard 7, may ultimately lead to
genetic mutations that trigger diseases such as
CML. 6
Throughout our research we discovered various
articles which linked potential carcinogenic
substances (e.g. benzene) to the development of
mutations in humans leading to various types of
leukemias. Some of the articles dated back to
1981 7, yet little action has taken place to
adequately prevent human exposure to these
harmful substances. In the case of benzene, the
maximum legal exposure level is dangerously close
to the concentration level which has been found
to cause genetic mutations in humans. The patient
in the case study was exposed to benzene while
working in a copy center for 5 years. During this
period it is likely that the patient suffered the
mutation that ultimately triggered CML, since the
diagnosis followed shortly thereafter. Despite
the fact that employers are advised that
employees might be exposed to carcinogenic
substances while working in a certain
environment, few of them respond appropriately.
Therefore stricter regulations should be enforced
by the government, in particular OSHA, to ensure
that employees are adequately protected.
Development of STI-571 opens the door to the
further development of anticancer agents which
are designed to target specific molecular
abnormalities in human cancer. Before development
of this drug, chemotherapy was a common option
used by healthcare practitioners for treating
CML. Chronic stage patients are no longer
restricted to following the harsh treatment of
chemotherapy including prolonged hospital stays,
intravenous injections, and severe side effects.
Despite progress in CML treatment, many of the
patients experience resistance to STI-571 either
from the beginning or throughout the course of
their treatment. New research is needed to
discover how to counteract the resistance.
Several new drugs are currently in phase three
clinical trials (conducted by the FDA) that may
prove to be more effective for treating patients
with resistance to STI-571. Throughout our
research we found that interest was focused on
the shortened 22nd chromosome abnormality, yet
nothing was mentioned regarding the elongated
9th. It would be interesting to find out whether
further mutations are induced by the elongated
9th chromosome, and what genes are potentially at
risk. 1 DAntonio, J. Chronic Myelogenous
Leukemia. Clinical Journal of Oncology Nursing.
9(5) 535-8. 2 Faderl et al. Oncology
(Huntingt). 1999 13169. 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 4937-46. 9
STI-571 in Chronic Myelogenous Leukaemia. British
Journal of Haematology. 2002 15-24.
Treatments
There are four principal therapeutic options
which are mainly classified as chemo therapy
(hydroxyurea and busulfan), interferon, imatinib,
and transplantation. While only transplantation
usually leads to complete recovery, its drawbacks
include a high risk of upfront mortality and
limited availability depending on donor
compatibility. 9 One of the newest discoveries
in the field of cancer treatment is the
development of STI-571 (Imatinib Mesylate), a
milestone in modern pharmacology because of its
ability to target specific molecules within cells
(rational drug design). It was designed to bind
to the Bcr-Abl tyrosine kinase molecule to impede
its binding to the ATP (Adenosine
5-triphosphate) molecule which would otherwise
signal the leukemic cell to reproduce. This
causes the leukemic cells to eventually die out
by apoptosy.
Fig. 2 Survival probabilities of patients in
Chronic Phase CML, following a-Interferon
failure. The probability of survival for those
treated with Imatinib Mesylate is significantly
higher than those who were not treated with it.
Imatinib information is only available for the
past 4 years (since its release).
Background
Accelerated and second chronic phase (n744)
National Marrow Donor Program overview slide
presentation. 4 http//www.marrow.org/NMDP/SLID
ESET/sld031.htm.
Case Study
The Philadelphia Chromosome
References
The patient was diagnosed with CML on December
21, 2004. The patient had a white blood count
(WBC) performed in February, 2004, however,
doctors did not conduct further tests despite
anomalous WBC levels and distribution. Therefore,
no additional tests were performed between
February 2004 and December 2004. This is
reflected in Figure 3 as a linear growth between
these dates, despite the fact that it is likely
that this growth would have been exponential due
to normal cell division patterns. On December 15,
2004, the patient was found to have an enlarged
spleen and had 4 blasts and 71,900 WBC, which
indicated a potential diagnosis for CML. After
bone marrow tests, the patient tested positive
for BCR-ABL expression (resulting from
Ph-chromosome) which is a clear indication of
CML.
Fig. 4 White Blood Count progression in subject
beginning one year before being diagnosed, and
continuing throughout the first year of treatment
with STI-571.
6 Pasternak et al. J Cancer Res Clin Oncol.
1998124643.