lecture 10 Flashcards

Question

What is the molecular pathogenesis of acute leukaemia?

Answer 1

chronic immune stimulation - several environmental agents that cause localised chronic immune stimulation predispose to lymphoid neoplasia, which almost always arises within the inflamed tissue - H. pylori infection and gastric B-cell lymphomas - Gluten-sensitive enteropathy and intestinal T-cell lymphomas Iatrogenic factors - radiation therapy and certain forms of chemotherapy used treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms - stems from the mutagenic effects of ionising radiation and chemotherapeutic drugs on hematolymphoid progenitor cells Smoking - the incidence of AML is increased 1.3- to 2-fold in smokers, due to exposure to carcinogens, such as benzene, in tobacco smoke

Answer 2

- human t-cell leukaemia virus-1 (HTLV-1) - epstein-barr virus (EBV) - kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8)

Answer 3

- the vast majority (85% - 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumours

Answer 4

- involve bone marrow and (usually, but not always) the peripheral blood

Answer 5

arise as discrete tissue 'tumours' - e.g. in lymph nodes

Answer 6

- abrupt stormy onset within days to a few weeks of the first symptoms - symptoms related to depression of marrow function, including fatigue due to anaemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia - mass effects caused by neoplastic infiltration (which are more common ALL), including bone pain resulting from marrow expansion; generalised lymphadenopathy, splenomegaly, a hepatomegaly; testicular enlargement; and in T-ALL, complications related to compression of large vessels and airways in the mediastinum - (not common)central nervous system manifestations such as headache, vomiting, and nerve palsies resulting from meningeal spread, all of which are also more common in ALL

Answer 7

- with aggressive chemotherapy about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured - however ALL remains the leading cause of cancer deaths in children, and only 35% to 40% of adults are cured

Answer 8

Acute lymphoblastic leukaemia/lymphomas - composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts - about 85% are B-ALLs, which typically manifest as childhood acute "leukaemias" - the less common T-ALLs tend to present in adolescent males and thymic "lymphomas"

Answer 9

- blood smear (morphology) - accumulation of 'blasts | - expression of particular markers/known receptors - e.g. intracellular TdT, CDs (22, 19, 10)

Answer 10

- approximately 90% of ALLs have numerical or structural chromosomal changes/mutations - with respect to gene mutations: single mutations are not sufficient to produce 'ALL' - studies of identical twins with concordant B-ALL: same mutation but different 'evolution' over time ie. further mutations required - many of the chromosomal aberrations seen in ALL d ysregulate the expression and function of transcription factors that are required for normal B- and T-cell development - T-ALLs - NOTCH1 TF - B-ALLs - PAX5, E2A, TFs

Answer 11

AML - more cytoplasm in blast cells - CD34, CD64, CD33, CD15 ALL - most taken up by nucleus - intracellular TdT, CDs (22, 19, 10)

Answer 12

- causes 1% of all cancer deaths in Western countries - Its incidence is higher in men and people of African descent - It is chiefly a disease of the elderly, with a peak age of incidence 65 to 70 years - plasma cell neoplasm characterised by multifocal involvement of the skeleton - less common manifests in lymph nodes and/or skin - normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing Ig

Answer 13

- in 99% of patients, laboratory analyses reveal increased levels of Igs in the blood and/or light chains (Bence Jones proteins) in the urine - the most common monoclonal Ig ("M protein") is IgG (~55% of patients), followed by IgA (~25% of cases) - myelomas expressing IgM, IgD, or IgE occur but are rare - you get a really thick band as opposed to a smear on gel electrophoresis

Answer 14

- the Ig genes in myeloma cells always show evidence of somatic hypermutation - the cell of origin is considered to be a post-germinal centre B cell that homes to the bone marrow and has differentiated into a plasma cell - may originate in and be maintained by stem-like cells resembling small B lymphocytes via oncogenic signals generated by the "hedgehog" pathway for self-renewal - a key factor promoting the proliferation and survival of myeloma cells is IL-6 via autocrine and paracrine signalling from stromal cells - factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma - myeloma-derived MIP1-alpha upregulates the expression of the receptor activator NF-kappaB ligand (RANKL) by bone marrow stromal cells, which in turn activates osteoclasts - further enhancing this effect is the Wnt-pathway mediated inhibition of osteoblasts

Answer 15

- prognosis is variable but generally poor - median survival is 4 - 6 years, and cures have yet to be achieved - patients with multiple bony lesions, if untreated, rarely survive for more than 6-12 months, whereas patients with "smouldering myeloma" may be asymptomatic for many years - translocations involving cyclin D1 are associated with a good outcome, whereas deletions of 13q, deletions of 17p, and the t(4;14) all require aggressive therapies - chemotherapy induces remission in 50% to 70% of patients

Answer 16

- defined by the presence of rearrangements in the anaplastic lymphoma kinase (ALK) gene - rearrangements break the anaplastic lymphoma kinase (ALK) locus and lead to the formation of chimeric genes encoding ALK fusion proteins, constitutively active tyrosine kinases that trigger a number of proliferation and survival signalling pathways, including the JAK/STAT pathway - the cure rate with chemotherapy is 75% to 80% - inhibitors of ALK are under development and offer an excellent opportunity for the development of a selective, targeted therapy - ALK-specific antigen vaccine

lecture 10 Flashcards

diseases of white blood cells and lymph nodes - to be able to give examples of major diseases covered in the lecture involving WBCs and lymph nodes - to gain an understanding of the signs, molecular basis and treatments of major diseases involving white blood cells and lymph nodes (40 cards)