BIOLOGY INVESTIGATORY PROJECT

● NAME: SWATHI SUKESH

THIS IS TO CERTIFY THAT MISS.

SIGNATURE OF SIGNATURE OF SIGNATURE OF

SCHOOL STAMP :
 ACKNOWLEDGEMENT
I wish to express my deep gratitude and sincere
thanks to my respected principal Dr.Prashant
Bukkawar at NHPS, New Panvel for this
encouragement and, for all the facilities that he
provide for this project work “Biology
Investigatory” which also encouraged me to do a lot
of research work and learn about new things.
I extend my hearty thanks to my subject teacher
Mrs. Beena Menon. I take this opportunity to express
my deep sense of gratitude, for her invaluable
guidance, constant encouragement which has
sustained my efforts at all stages of this project
work.
I cannot forget to offer my sincere thanks to my
parents and friends who helped me a lot in finalising
this project.
 INDEX

CONTENTS:

● ACKNOWLEDGEMENT

● CERTIFICATE

● INTRODUCTION

● SIGNS AND SYMPTOMS

● CAUSE

● PATHOPHYSIOLOGY

● DIAGNOSIS

● TREATMENT

● EPIDEMIOLOGY

● BIBLOGRAPHY
 INTRODUCTION
Chronic myeloid leukemia (CML), also
known as chronic myelogenous
leukemia, is a cancer of the white blood
cells. It is a form of leukemia characterized
by the increased and unregulated growth of
myeloid cells in the bone marrow and the
accumulation of these cells in the blood.
CML is a clonal bone marrow stem cell
disorder in which a proliferation of mature
granulocytes (neutrophils, eosinophils and
basophils) and their precursors is found. It
is a type of myeloproliferative neoplasm
associated with a characteristic
chromosomal translocation called the
Philadelphia chromosome.
 SIGNS AND SYMPTOMS
The way CML presents depends on the stage
of the disease at diagnosis as it has been
known to skip stages in some cases. Most
patients (~90%) are diagnosed during the
chronic stage which is most often
asymptomatic. In these cases it may be
diagnosed incidentally with an elevated white
blood cell count on a routine laboratory test. It
can also present with symptoms indicative of
hepatosplenomegaly and the resulting upper
quadrant pain this causes. The enlarged spleen
may put pressure on the stomach causing a
loss of appetite and resulting weight loss. It
may also present with mild fever and night
sweats due to an elevated basal level of
metabolism.Some (<10%) are diagnosed
during the accelerated stage which most often
presents bleeding, petechiae and ecchymosis.
In these patients fevers are most commonly
the result of opportunistic infections. Some
patients are initially diagnosed in the blast
phase in which the symptoms are most likely
fever, bone pain and an increase in bone
marrow fibrosis.
CAUSE
In most cases no obvious cause for CML can
be isolated.
Risk factors
CML is more common in males than in
females (male to female ratio of 1.4:1) and
appears more commonly in the elderly with
a median age at diagnosis of 65 years.
Exposure to ionising radiation appears to
be a risk factor, based on a 50 fold higher
incidence of CML in Hiroshima and
Nagasaki nuclear bombing survivors. The
rate of CML in these individuals seems to
peak about 10 years after the exposure.
 PATHOPHYSIOLOGY
CML was the first cancer to be linked to a
clear genetic abnormality, the chromosomal
translocation known as the Philadelphia
chromosome. This chromosomal
abnormality is so named because it was
first discovered and described in 1960 by
two scientists from Philadelphia,
Pennsylvania, USA: Peter Nowell of the
University of Pennsylvania and David
Hungerford of Fox Chase Cancer Center. In
this translocation, parts of two
chromosomes (the 9th and 22nd) switch
places. As a result, part of the BCR
("breakpoint cluster region") gene from
chromosome 22 is fused with the ABL gene
on chromosome 9. This abnormal "fusion"
gene generates a protein of p210 or
sometimes p185 weight (p210 is short for
210 kDa protein, a shorthand used for
characterizing proteins based solely on
size).

DIAGNOSIS
CML is often suspected on the basis of a
complete blood count, which shows
increased granulocytes of all types, typically
including mature myeloid cells. Basophils
and eosinophils are almost universally
increased; this feature may help
differentiate CML from a leukemoid
reaction. A bone marrow biopsy is often
performed as part of the evaluation for
CML, and CML is diagnosed by cytogenetics
that detects the translocation which
involves the ABL1 gene in chromosome 9
and the BCR gene in chromosome 22. As a
result of this translocation, the
chromosome looks smaller than its
homologue chromosome, and this
appearance is known as the Philadelphia
chromosome chromosomal abnormality.
Thus, this abnormality can be detected by
routine cytogenetics, and the involved
genes BCR-ABL1 can be detected by
fluorescent in situ hybridization, as well as
by PCR.]
Controversy exists over so-called Ph-
negative CML, or cases of suspected CML in
which the Philadelphia chromosome cannot
be detected. Many such patients in fact have
complex chromosomal abnormalities that
mask the translocation, or have evidence of
the translocation by FISH or RT-PCR in
spite of normal routine karyotyping. The
small subset of patients without detectable
molecular evidence of BCR-ABL1 fusion
may be better classified as having an
undifferentiated
myelodysplastic/myeloproliferative
disorder, as their clinical course tends to be
different from patients with CML.
CML must be distinguished from a
leukemoid reaction, which can have a
similar appearance on a blood smear.
 TREATMENT
The only curative treatment for CML is a
bone marrow transplant or an allogeneic
stem cell transplant. Other than this there
are four major mainstays of treatment in
CML: treatment with tyrosine kinase
inhibitors, myelosuppressive or
leukopheresis therapy (to counteract the
leukocytosis during early treatment),
splenectomy and interferon alfa-2b
treatment. Due to the high median age of
patients with CML it is relatively rare for
CML to be seen in pregnant women, despite
this, however, chronic myelogenous
leukemia can be treated with relative safety
at any time during pregnancy with
Interferon-alpha hormones.
Chronic phase
In the past, antimetabolites (e.g., cytarabine,
hydroxyurea), alkylating agents, interferon
alfa 2b, and steroids were used as
treatments of CML in the chronic phase, but
since the 2000s have been replaced by Bcr-
Abl tyrosine-kinase inhibitors drugs that
specifically target BCR-ABL, the
constitutively activated tyrosine kinase
fusion protein caused by the Philadelphia
chromosome translocation. Despite the
move to replacing cytotoxic antineoplastics
(standard anticancer drugs) with tyrosine
kinase inhibitors sometimes hydroxyurea is
still used to counteract the high leukocyte
counts encountered during treatment with
tyrosine kinase inhibitors like imatinib; in
these situations it may be the preferred
myelosuppressive agent due to its relative
lack of leukemogenic effects and hence the
relative lack of potential for secondary
hematologic malignancies to result from
treatment. IRIS, an international study that
compared interferon/cytarabine
combination and the first of these new
drugs imatinib, with long-term follow up,
demonstrated the clear superiority of
tyrosine-kinase-targeted inhibition over
existing treatments.
Treatment-resistant CML
While capable of producing significantly
improved responses compared with the
action of imatinib, neither dasatinib nor
nilotinib could overcome drug resistance
caused by one particular mutation found to
occur in the structure of BCR-ABL1 known
as the T315I mutation (i.e. where the 315th
amino acid is mutated from a threonine
residue to an isoleucine residue). Two
approaches were developed to the
treatment of CML as a result:
In 2007, Chemgenex released results of an
open-label Phase 2/3 study (CGX-635-CML-
202) that investigated the use of a non BCR-
ABL targeted agent omacetaxine,
administered subcutaneously (under the
skin) in patients who had failed with
imatinib and exhibited T315I kinase
domain mutation. This is a study which is
ongoing through 2014. In September 2012,
the FDA approved omacetaxine for the
treatment of CML in the case of resistance
to other chemotherapeutic agents.
Independently, ARIAD pharmaceuticals,
adapting the chemical structures from first
and second-generation TK inhibitors,
arrived at a new pan-BCR-ABL1 inhibitor
which showed (for the first time) efficacy
against T315I, as well as all other known
mutations of the oncoprotein. The drug,
ponatinib, gained FDA approval in
December 2012 for treatment of patients
with resistant or intolerant CML. Just as
with second generation TK inhibitors, early
approval is being sought to extend the use
of ponatinib to newly diagnosed CML also.
Vaccination
In 2005, encouraging but mixed results of
vaccination were reported with the
BCR/ABL1 p210 fusion protein in patients
with stable disease, with GM-CSF as an
adjuvant.

EPIDEMIOLOGY
United Kingdom
CML accounts for 8% of all leukaemias in
the UK, and around 680 people were
diagnosed with the disease in 2011.
United States
The American Cancer Society estimates that
in 2014, about 5,980 new cases of chronic
myeloid leukemia were diagnosed, and
about 810 people died of the disease. This
means that a little over 10% of all newly
diagnosed leukemia cases will be chronic
myeloid leukemia. The average risk of a
person getting this disease is 1 in 588. The
disease is more common in men than
women, and more common in whites than
African-Americans. The average age at
diagnosis is 64 years, and this disease is
rarely seen in children.

BIBLOGRAPHY
 Wikipedia
 cancer.org
 webmd.com