Transcript Acute Leukemia and the FLT3

Acute Leukemia and the FLT3 Receptor
By: Betty Sa’
Mentor: Dr. Govind Bhagat
Site: Columbia University
Vanderbilt Clinic
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Leukemia is a cancer of the blood in which immature
hematopoietic cells proliferate in an uncontrolled manner.
Leukemia originates in the bone marrow and quickly
spreads elsewhere. There are four major types of Leukemia,
Acute Myeloid Leukemia (AML), Acute Lymphoblastic
Leukemia (ALL), Chronic Myeloid Leukemia, and Chronic
Lymphocytic Leukemia. But we are only focusing on AML
and ALL. Acute means that the disease appears quickly and
advances rapidly, so patients with ALL and AML usually
require immediate treatment.
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Acute Lymphocytic Leukemia (ALL) is a rapidly progressing disease marked by the
overabundance of immature lymphoid cells (lymphoblasts) in the blood or bone
marrow; most commonly found in children. Healthy lymphocytes fight bacterial and
viral infections. But in patients with ALL the lymphocytes do not develop into mature
cells, and remain immature cells called lymphoblasts. In this type of Leukemia blood
cells differentiation and gets stuck at the lymphoblast stage and continues proliferation.
So the abnormal cells crowd the normal cells in the bone marrow and prevent the
production of red blood cells, other white blood cells, and platelets. This causes most
ALL patients to become anemic, susceptible to infection, and bruise or bleed easily.
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Acute Myeloid Leukemia (AML) is a cancer in which there is uncontrollable growth of
immature myeloid cells (myeloblasts, promyelocytes, monoblasts, erythroblasts,
megakaryoblasts) in the bone marrow that leads to a deficiency of red blood cells,
platelets, and white blood cells. In these types of Leukemia blood cell differention gets
stuck at various stages of myeloid, monocytic, erythroid, or megakaryocytic
differentiation and these cells continue to proliferate.
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There are different sub-types of AML, depending upon exactly which type of cell
has become leukemic the stage of maturation the cells are at and whether the cells
are differentiated, these sub-types include: Acute Myeloid Leukemia without
maturation, Acute Myeloid Leukemia with maturation, Acute Promyelocytic
Leukemia (APL), Acute Myelomonocytic Leukemia, Acute
Monocytic/Monoblastic Leukemia, Acute Erythroleukemia, and Acute
Megakaryoblastic Leukemia.
In AML where the granulocytic (neutrophilic) series is affected, there is a block
in the production of mature neutrophils. Neutrophilis fight infections caused by
bacteria. The production of mature neutrophilis is usually tightly regulated.
Mature neutrophilis develop from less mature white cells in a process called
differentiation. In AML, acquired mutations in the blood-forming cells disrupt the
normal process of differentiation, resulting in the accumulation of large members
of immature cells called myeloblasts. If the erythroid lineage is affected, blasts
cannot function like fully developed, healthy red blood cells. The large number of
blasts also reduces the production of healthy red blood cells and platelets. So,
patients are usually anemic.
ALL
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FLT3 stands for FMS-like tyrosine kinase 3 gene, which encodes a
membrane-bound receptor tyrosine kinase (RTK) that has a crucial
role in normal haematopoiesis.
Normally, FLT3 expression is restricted to CD34+ hematopoietic
stem/progenitor cells, brain, placenta, and gonads. Activation of FLT3
by FLT3-Ligand promotes the normal, in vitro growth of early
progenitor cells.
In Acute Leukemia, mutations of the FLT3 gene have been found to
be one of the most common acquired genetic lesions. FLT3 mutations
can be detected in 30% of AML patients. There are two frequent
types of somatic FLT3 genetic mutations: internal tandem duplications
(ITDs) in the juxtamembrane (JM) domain and point mutations in the
activation loop of the tyrosine kinase domain (TKD).
Studies have shown that ITD mutations are triggered by any
elongation or shortening of the JM domain of FLT3 due to additions or
deletions of amino acids that result in the constitutive activation of
FLT3. The presence of FLT3/ITD mutations is associated with a poor
clinical outcome in both pediatric and adult patients with AML.
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Point mutations in the activation loop of the kinase domain
(FLT3/TKD) involves the aspartic acid, D835 residue,
which leads to an activated configuration and transformation
of myeloid cells. D835 mutations are missense mutations
that results in substitution of tyrosine, histidine, valine,
glutamic acid or asparagine for aspartatic acid at amino acid
835 of FLT3.
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This mutation has been reported in 7% of patients with
AML. TKD mutations, unlike ITD mutations, have not been
shown to have any prognostic significance in AML patients.
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Both types of FLT3 mutation cause ligand-independent
activation of the receptor and activation of downstream
signaling pathways.
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In 2006 an estimated 3,930 adults (2,150 men and 1,780 women) in the
US will be diagnosed with ALL and an estimated 1,490 (900 men, 590
women) deaths will occur. ALL is more common in adults older than
50. 20% to 30% of adults with ALL experience long-term disease
remission or are cured of the disease.
ALL is more common in children than in adults; 74% of all new cases
are diagnosed in children ages 0 to 19.
In 2006, an estimated 11,930 people (6,350 men and 5,580 women) in
the US will be diagnosed with AML and an estimated 9,040 deaths will
occur (5,090 men and 3,950 women). AML is most common in older
adults around 60-65 years old.
The percentage of patients who survived at least five years after being
diagnosed, for adults under the age 65 with AML is 33%.
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To get a better understanding of the molecular
abnormalities underlying Acute Leukemia's.
I will study the different types of FLT 3 tyrosine
kinase mutations in subsets of acute leukemias to
determine their relative frequency and impact on
the biologic course of disease .
I will also correlate the presence of FLT3 mutations
with other cytogenetic abnormalities in different
types of acute leukemias to better understand the
multi-step pathways of leukemogenesis.
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Case selection – Acute leukemias diagnosed at
Columbia University Medical Center over the past 5
years for which cytogenetic information is available
(at least 100 cases)
DNA extraction from peripheral blood or bone marrow
aspirate samples
PCR using primers specific for certain portions of the
FLT3 gene
Capillary gel electrophoresis
Analysis of spectrophoretograms for FLT3 TKD and
FLT3-ITD mutations
http://www.dsrct.demon.co.uk/cells.jpg
www.nature.com/reviews/cancer
www.vghtpe.gov
www.health.sa.gov.au/cancare
www.elsevier.com/locate/biocel
www.sciencedirect.com
health.on-topic.net/health/Acute+Lymphocytic+...
Dr. Govind Bhagat
 Dr. Mahesh Mansukhani
Columbia University
 Dr. Sat
MSKCC
 Harlem Children Society
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