Transcript Leukaemia
Importance of Haematological Malignancies Clinical Relatively common in younger people Treatment frequently successful Beacon for other malignancies Scientific Ease of tissue access Illustration of important concepts Single cell origin of malignancy Stem cell origin of leukaemia Variable differentiation block and relationship to phenotype Frequency of balanced translocations which help identify ‘proto-oncogenes’. Curability of Haematological Malignancies Chances of Long-term Disease Free Survival in a 5 year old and 30 year old with: Acute Lymphoblastic Leukaemia Acute Myeloid Leukaemia Hodgkin Lymphoma Non-Hodgkin’s Lymphoma 5years 85% 60% 90% 85% 30 years 25% 45% 85% 60% (high grade) Importance of Haematological Malignancies Clinical Relatively common in younger people Treatment frequently successful Beacon for other malignancies Scientific Ease of tissue access Illustration of important concepts Single cell origin of malignancy Stem cell origin of leukaemia Variable differentiation block and relationship to phenotype Frequency of balanced translocations which help identify ‘protooncogenes’. Access to Haematological Tissues Bone Marrow Stem cells and Haemopoiesis Early lymphopoiesis Blood Mature blood cells Immature cells in leukaemia Lymph nodes Later lymphopoiesis Aspirate and trephine biopsies Venesection Lymph node aspirates Lymph node excision Importance of Haematological Malignancies Clinical Relatively common in younger people Treatment frequently successful Beacon for other malignancies Scientific Ease of tissue access Illustration of important concepts Single cell origin of malignancy Stem cell origin of leukaemia Variable differentiation block and relationship to phenotype Frequency of balanced translocations which help identify ‘protooncogenes’. Clonal Origins of Malignancies Disease and individual specific cytogenetic abnormalities in all cells. Immunoglobulin light chain restriction in B-cell malignancies Useful in differential diagnosis of a marginal lymphocytosis Useful in differential diagnosis of some lymphomas Importance of Haematological Malignancies Clinical Relatively common in younger people Treatment frequently successful Beacon for other malignancies Scientific Ease of tissue access Illustration of important concepts Single cell origin of malignancy Stem cell origin of leukaemia Variable differentiation block and relationship to phenotype Frequency of balanced translocations which help identify ‘protooncogenes’. The Haemopoietic system Stem cells progenitors lymphoid stem cell precursors mature cells T cells, B cells etc RBC Pluripotent Stem cell myeloid stem cell platelets Megakaryocyte Neutrophil Macrophage Eosinophil Hierarchy of haemopoietic cells Stem cells Detectable by in vivo assays in animals. Progenitor cells Detectable by in vitro assays Eg Colony forming assays Precursor cells End cells Morphologically Recognisable. Fully differentiated Short life span. CD34- Colony formation in semi-solid media Haemopoietic progenitors depend on external cues for growth and survival Growth factors SCF, Tpo, FL Other regulators Jagged, Wnt Stromal cells ECM components Fibronectin, GAGs Inhibition of basal progenitor cell apoptosis by raised epo levels promotes rapid red cell expansion during stress steady-state epo levels elevated epo levels Neutrophil/RBC/platelets lymphocyte monocyte Classification of leukaemia • Acute Malignant cells have a primitive phenotype Disease generally progresses quickly Often bone marrow failure at presentation - clinical features due to this • Chronic Excess proliferation of more mature cells Clinical features due to cellular burden: eg gout, organomegaly Bone marrow failure a late feature Classification of leukaemia Acute Chronic Myeloid AML CML Lymphoid ALL CLL Pathogenesis: Acute leukaemia Block at an early stage of differentiation Accumulation of immature cells Stem cell x lack of mature cells Pathogenesis: Chronic myeloid leukaemia Stem Cell Excessive proliferation leads to accumulation of functional mature cells Chronic Myeloid Leukaemia Multi-step pathogenesis of malignancy Initiating events Immortalisation Differentiation block Growth advantage Survival advantage Secondary events Importance of Haematological Malignancies Clinical Relatively common in younger people Treatment frequently successful Beacon for other malignancies Scientific Ease of tissue access Illustration of important concepts Single cell origin of malignancy Stem cell origin of leukaemia Variable differentiation block and relationship to phenotype Frequency of balanced translocations which help identify ‘protooncogenes’. Mechanisms of Reciprocal Translocations DSBs Common molecular lesions in leukaemias ``` Gene AB Gene A Gene B ``` Gene BA Detect by cytogenetics, southern blot or PCR Results in expression of target gene in an inappropriate tissue, at the wrong time in development or in the wrong cellular location Examples Bcr-Abl in CML PML-RARA in AML M3 type Common molecular lesions in B-cell lymphomas Normal B-cell lymphoma B-cell Immunoglobulin promoter ` Proliferation/survival gene Proliferation/survival protein Examples IgH-Myc in Burkitt lymphoma IgH-Bcl-2 in follicular lymphoma