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Molecular Hematology
Galila Zaher
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DNA RNA Protein
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DNA & RNADNA RNADouble-stranded Single-stranded4 bases: A, C, G & T A, C, G & USugar: Deoxribose Sugar: RiboseStable molecule Unstable moleculeIntrons + Exons Introns
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DNA: Building Blocks
Purine
Pyrimidine
BasesPurinesAdenine
GuaninePyrimidinesCytosine
Thymine[Uracil]
Purine ‘pair’ pyrimidine
Adenine-Thymine
Guanine-Cytosine
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DNANature paper here
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ChromosomesMale karyotype
46:XY
Female karyotype
46:XX
22 pairs of autosomes + 1 pair sex chromosomes
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Normal StructureSomatic cell has 46 chromosomes : diploid.Ova and sperm have 23
chromosomes :haploid.Karyotype shows chromosomes of dividing
cell in numerical order.
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Chromosome has two arms:
Short arm = p Long arm = q.
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Short and long arms meet at the Centromere.
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Ends of the chromosomes are called Telomeres
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Each arm is divided into regions numbered from centromere.
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Each region is divided into bands.
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Numerical Abnormality Aneuploid: Somatic cell with >or <46
chromosomesA. Hyperdiploid: >46 chromosomesB. Hypodiploid : <46 chromosomes. Pseudodiploid: 46 chromosomes but with
rearrangements.
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Structural Abnormalitydel : deletion where part of chromosome is lost
del(16q).Add: additional material has replaced part of a Cht: Translocation t(9; 22)inv :inversion; part of Ch runs in opposite direction.Point mutationNon sense :Result in creation of premature stop codon
Normal sequence ATG CTG TGC CysMutant sequence ATG CTG TGA stop
i: isochromosome is a chromosome with identical chromosome arms at each end, e.g. i(17q) has two copies of 17q joined at centromere.
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Haematological MalignanciesMostly clonal disorders resulting from a genetic
alteration.Tumor-Suppressor Genes : inhibit expression
of tumor phenotype. When are inactivated or lost abnormal proliferation
Oncogenes :Genes which can potentially induce neoplastic transformation. They include genes for growth factors, growth factor receptors, protein kinases,etc.
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Normal proliferation / ApoptosisExcess proliferation / loss of Apoptosis
Tumour-suppressorgene
OncogeneProto-oncogene
Tumour-suppressorgene
Genetics of Haematological Malignancies
Mutation
Mutation or deletion
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Clonal ProgressionActivation of OncogenesInactivation of Tumour-Suppressor GenesMalignant cells acquire new characteristics
causing acceleration.Multidrug resistance (MDR) is one
complication. Cells start to express a protein which actively pumps chemotherapeutic agent to outside of cells.
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Thalassemia Heterogenous group of genetic disorders
Mutation decrease rate of synthesis of globin chains ( or ).
0 :complete absence of chain . Common in Mediterranean.
+ :partial block in chain synthesis. 1. Noncoding introns inefficient RNA splicing ,decreased
mRNA production2. Promoter leading to decreased expression3. Termination site production of longer, unstable mRNA
Partial or total deletion of a globin gene thalassemia major :0/0, +/ +, or 0/ +
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ß-ThalassemiasDisease manifests itself when switch chain ms
after birth Imbalanced synthesis low Hb production, MCV &
MCH Excess chains precipitate in RBC precursors in bone
marrow leading to hemolysis and ineffective erythropoiesis
Excess chains in circulating RBCs precipitate leading to pitting in spleen & RBC survival via a chronic hemolytic process.
The major cause of severe anemia is the ineffective erythropoiesis.
Compensatory increase in & chain synthesis Hb F& A2.
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Hereditary thrombophiliaPCPSATProthrombin Gene Mutation:G20210A. Factor V Leiden Mutation: R506Q.MTRFR :mutation
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INHERITED RISK FACTORS INHERITED RISK FACTORS Relative risk of VTERelative risk of VTE
0
20
40
50
Heterozygous deficiency of AT,
PC, PS
Heterozygous G1691A FV
Homozyougs G1691A FV
Heterozygous G20210
prothrombin
Homozyg prothrombin
10-fold 5- to 8-fold
50- to 80- fold
30
60
70
80
2-to 4- fold 10- fold
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Gene Structure
Splice sites
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X-linked DisordersHaemophilia A and BX-linked disordersMales affected –
females carriers
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Queen Victoria (1819 - 1901)
Queen Victoria Queen of England from 1837 to 1901 was a carrier.
Her eighth child, Leopold, had Hemophilia and suffered from frequent hemorrhage.
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Descendants Eugenie, who was a carrier introduced Hemophilia into Spanish royal family .
Irene married to Prince Henry of Prussia introduced the disease into the German royal family
Alexandra married Russia's last czar Nicholas II introduced the disease into the Russia royal family, which ultimately played a role in the start of the Russian Revolution.
Royal Disease
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Alexis, son of Nicholas and Alexandra (1904 - 1918)
Alexandra gave birth to a son Alexis the long awaited heir Russian throne.
Unfortunately Alexis had Hemophilia which ultimately played a role in the start of the Russian Revolution.
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Victoria will be remembered as the cause of Hemophilia which spread to the Royal Family of Europe through her descendants
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F8 Gene
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FIX Gene
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Types of MutationsMissense mutationsNonsense mutationsSplice mutationsInsertionsDeletions
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Inversions Sever HASHA: Intron 22: ~50% cases Intron 1: <1% cases
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Haemophilia A: Intron 22 Inversion
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Cytogenetic &Molecular studies• Karyotype Analysis (numerical ) • Immunofluorescence Staining
(structural)• Fluorescent in situ Hybridisation (FISH)• Southern Blot Analysis• Polymerase Chain Reaction (PCR)
t(9,22),hemophilia,thrombophilia• DNA Microarray Platforms
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ChromosomesMale karyotype
46:XY
Female karyotype
46:XX
22 pairs of autosomes + 1 pair sex chromosomes
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