بسم ا الرحمن الرحــــــيم Leukemia Course- Lecture #1
LEUKEMIAS Etiology and introduction Akram Al-Hilali 2009 08/06/14
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CANCER • Definition of Cancer • When does a cell become malignant? • Where does cancer start? • What starts a cancer process. • Body defenses against cancer
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DEFINITION OF CANCER Disease condition in which a cell line in a tissue starts to multiply in excess of the body need, progressively, without benefit to the body or control by its mechanisms. All cancers start with a change in a gene or genes 08/06/14
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ONCOGENES • What is an oncogene? • Oncogenes are normally present in our DNA. • They play very useful and important roles. • There are also oncogene inhibitors or tumour-suppressor genes. • What makes an oncogene bad? • Is an abnormal oncogene inherited?
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CELL WALL
Ligand
CYTOPLASM NUCLEUS
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Normal vs. abnormal Oncogenes • What does a normal oncogene do?
– Produce a kinase, commonly tyrosine kinase, that works as signal transducer for cell division. – Produces a factor that indirectly affects cell division in another type of cell. – All this is balanced and under control.
• Abnormal oncogene
– If product of the gene is increased in an uncontrolled manner it can induce ongoing division of target cells. – If there is a change in structure of one factor in the signaling mitogenic pathway, as a result of gene change, that makes the factor autonomous then the process will start and never end, regardless of the growth factor. 08/06/14
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What causes change in the ?oncogene • Any gene could be modified during life by various mutagenic agents. • Chemotherapy, irradiation, chemical from smoking, food additives and viruses can modify a gene. • The resulting modification can kill the cell, inhibit its growth or make the oncogene malignant, depending on where the gene “event” occurs. • The faster the mitosis rate in a cell the more likely it is that mutation can occur 08/06/14
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Examples of Abnormal Oncogenes
How does an oncogene become abnormal?
– It may become amplified, thus producing more of the kinase. Examples are • • • •
N-myc in neuroblastoma, L-myc in small cell lung carcinoma Her-2 in Ca breast WT-1 amplification by Trisomy 8 in some MDS cases
– It may join another oncogene and fuse with it as a result of translocation with resulting hyperactive fusion gene product. Example is • fusion gene (BCR-ABL) produced in t(9;22)in CML and other leukemias • Fusion gene PML-RARα produced by t(15;17) of PML 08/06/14
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Examples of abnormal oncogenes • An oncogene may get mutated with resulting increased activity, as in FLT3 (13q12) and CEBP-A, WT1 mutations, NPM1, etc. • An anti-oncogene may get lost with a deletion of chromosome segment that carries the gene or loss of the chromosome altogether, as in Del (5q), Del(7q), monosomy 7 and Del(9q). 08/06/14
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Abnormal Oncogenes.Contd – An anti-oncogene may become mutated and stops working. Example is • Deletion of 13q14 in multiple myeloma and NHL, making its prognosis worse. • P53 mutation: common to many cancers
– Role of inhibited Programmed Cell Death (Apoptosis) genes in some leukemias. Fas-mediated apoptosis could be inhibited in leukemia and stimulated in some MDS cases. – Role of angiogenesis genes. – A gene of one factor in the pathway, including receptor of GF, may become modified in such a way as to make it autonomous. Examples are changes in Mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) in some cancers. – Some abnormal oncogenes do not initiate cancer but arise later in the course, to make it more aggressive.
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TELOMERES AND TELOMERASE • Telomeres are segments with repeated nucleotide sequences at the end of all chromosomes. • Decrease in telomere length with successive mitoses. • Telomerase is an enzyme that tends to add nucleotides at the ends of chromosomes to keep telomere length. • Weaker telomerase with successive mitoses. • Possible effect in chromosome breakages and translocations. Implicated in aging, cancer frequency and transformation from chronic to acute leukemia. 08/06/14
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?Can a virus cause cancer • In lower mammals and birds many cancers are caused by viruses. • In humans viral oncogenes may be playing roles in some cancers. Like Human papilloma virus (HPV) infection in uterine cervical cancer and Epstein-Barr virus infections in pharyngeal cancer. 08/06/14
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ROLE OF BODY DEFENSES • There are numerous evidences that diminished body defenses allow for cancer to arise more easily. • There is no doubt that body immune system eliminates many cancers arising before they become manifest. • Old age, immune-suppressive drug use, immunodeficiency conditions all have higher incidence of cancer. • Modified immune system may allow or initiate cancer process. Abnormal self-reacting clones of T lymphocytes have been implicated as initiator of MDS pathology in some MDS cases. • Response to anti-thymocyte therapy in many MDS cases.
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How does all this apply to ?Leukemias • Speed of mitosis will decide whether the leukemic cell has the time to get mature. • This will give acute versus chronic leukemia. • The leukemic cells will inherit from original malignant cell most of its immunologic, genetic and morphologic characters. This is the feature of any clonal disorder. • If ALL arises from a cell which has already acquired CD19, all offspring cells will be CD19+ • An acute or chronic leukemia may get a novel oncogene mutation during its course and become more aggressive or change to acute. 08/06/14
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It is agreed that Cancer can arise only from the Effect of many factors working together. An inherited gene+ mutated gene+ lost anti-oncogene + drop or change in Immunity is a sample collection of factors that may lead to initiation of cancer 08/06/14
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SELF RENEWAL VS. APOPTOSIS IN NORMAL Maturation Blasts
Apoptosis and cell death
Self renewal
SYMMETRICAL GROWTH
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IN ACUTE LEUKEMIA Blasts
Little or no maturation
Little or no apoptosis
Maturation arrest Continuous division and accumulation
ASYMETRICAL GROWTH
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IN CHRONIC LEUKEMIAS BLASTS Maturation Delay
ell C ed t a iv t c A
Decreased Apoptosis
n o i s i Div
SEMI-SYMETRICAL GROWTH
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