Genetics in Haematological Malignancies Lecture PDF

Genetics in haematological malignancies Dr Penny Keene The hallmarks of cancer Hanahan and Weinberg, Cell, 2000, updated 2011 1. Growth pathways must be increased in activity The genes for the components of these pathways are known as...

Genetics in haematological malignancies Dr Penny Keene The hallmarks of cancer Hanahan and Weinberg, Cell, 2000, updated 2011 1. Growth pathways must be increased in activity The genes for the components of these pathways are known as Oncogenes when they, or the proteins they code for, are inappropriately active  2. Decreased function of growth- inhibiting pathways Tumour suppressor genes  3. Inhibition of apoptosis Increasing the size of a cell population:  4. Immortalisation Not living forever but being able to continue dividing forever Telomere  5. Angiogenesis  6. Invasion Main mass Cancer of invadin cancer g tissue  6. … and metastasis Lymp h node Liver 7. Cancer cell metabolism – the Warburg effect 8. Evasion of the immune system Arrow: cance cells Arrowhead: lymphocytes  The hallmark changes do not have to occur in this order  Cancer: The “right” combination of mutations and epigenetic changes in a single cell Acute leukaemia – at least 1 proliferative change and 1 inhibiting maturation Haematological malignancies have fewer mutations than most solid tumours Adapted from Postgraduate Types of genetic changes involved in haematological cancer Epigenetics – either due to mutations of epigenetic control genes themselves or other genes which enable the function of the pathways. This may cause secondary changes in the expression of any of the genes involved in the hallmarks. Mutations or alterations of expression of the genes controlling hallmark functions  In at least 50% of acute myeloblastic leukaemias in adults “Cytogenetically normal there are NO AML” cytogenetically detectable abnormalities. Adapted from: Postgraduate Haematology Hoffbrand, Higgs et al Effects of translocati ons  Enabling characteristics: Hanahan and Weinberg, Cell, 2000, updated 2011 Genetic instability Inflammation The concept of clonal evolution Examples of important mutations in haematological malignancies IgH promoter Core binding factors Tyrosine kinases – FLT3, JAK, BCR-Abl Epigenetics –DNMTs and histone modifiers, MLL  IgH promoter in lymphoma Burkitt’s lymphoma - cMYC Mantle cell lymphoma – cyclin D1 Follicular lymphoma – BCL2  Core binding factor abnormalities in AML CBF is a transcription factor made of a heterodimer and is involved in the transcription of a number of important haemopoietic genes. Translocations leading to fusion proteins with either of the heterodimer partners interfere with the function of the transcription factor. These are important recurring genetic abnormalities in acute leukaemias. t(8;21 ) t(16;16) FMS-like tyrosine kinase 3 (FLT3) mutations: 1. FLT3 ITD of juxtamembrane region – 25% adult AML 2. FLT3 mutation in the kinase domain Increase d in ITD NPM1 mutations – 30% of AML Normal function is to increase P53 Mutated NPM moves to the cytoplasm. P53 is degraded. Caspases are inhibited. Centrosome replication is destabilised.  α ketoglutarate from the Kreb’s cycle Demethyla tion of cytosine in CpG Active demethylation 30% mutated From mutant IDH enzymes  Aberrant histone modification – MLL fusion proteins Normal function is to enhance HOX A gene transcription – this maintains haemopoietic stem cells. In this case the co-recruitment of  Why is this important? Classification of malignancies is now dependent on the molecular lesions/mutations present. Classification in turn leads to correct treatment. Precision medicine is dependent on knowing exactly what drives the cancer.