Lecture 5 - Leukemia: Pathogenesis And Pathophysiology Flashcards Preview

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Flashcards in Lecture 5 - Leukemia: Pathogenesis And Pathophysiology Deck (16)
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1

Leukemia

- a malignant proliferation of cells that arises following mutation within a single hematopoietic cell
- infiltate bone marrow and interfere with marrow function
- usually circulate in blood

2

Embryonic stem cell

- can create any tissue in the body
- derived from inner cell mass of early embryos
- ethicallyu ambiguous
- no specific phenotype

3

Hematopoietic stem cells

- can create any type of blood cell and probably bone, cartilage and fat
- found principahlly in bone marrow in adulthood, can also be collected from umbilical cord blood of newborks
- can be safely harvested and without ethical concerns
- currently thought to be at the highest concentration in the CD34+ population

4

Leukemia categories
- acute vs chronic
- myeloid vs lymphoid

- acute: likely to die within weeks if untreated but cure possible
- chronic have a much more indolent course, large number of patients dont require treatment at all

- AML, CML, ALL, CLL

5

Acute leukemia etiology

- hereditary: don't really run in families but associated with bloom's syndrome, Fanconi anemia, Down's syndrome, atacia telangiectasia, Wiskott-Aldrich syndrome
- Anteedent stem cell disorder: myeloproliferative neoplasms, nyelodysplastic syndromes, aplastic anemia, PNH
- chemicalsL benzene, organic solvents
- cytotoxic agents: alkylating agents, topoisomerase II inhibitors
- Radiation: atomic bomb, radiation therapy, electromagnetic radiation
- viruses: HTLV-1, HTLV-2

6

Bone marrow trephine findings

- much more hypercellular, fat spaces nearly disappeared
- BM fails because taken over by leukemia

7

Bone marrow aspirate findings

- monomorphic cells
- cells all look the same: large, big, more nucleate
- get rid of healthy hematopoietic cells

8

Consequences of leukemia

- bone marrow failure
- infiltration by leukemic cells
- systemic effects

9

Bone marrow failure syndrome

- failure of Haematopoietic cell function -> impaired red cell, white cell and platelet production
- many causes including: marrow infiltration by malignancy or rarely infection, bone marrow damage by immune or chemical agents, ionizing radiation
- marrow failure is common in leukemia

10

Clinical consequences of bone marrow failure

- anemia: impaired red cell production, fatigue, pallor, dyspnoea, cardiac failure
- leucopenia: impaired granulocyte and monocyte production, lack of phagocytosis of micro-organisms, fever, infections
- thrombocytopenia: bruising, bleeding, risk of serious GIT or CNS bleeding

11

Other clinical and heamatological features

- infiltration: leukostasis, bone pain, CNS involvement, hepatosplenomegaly, lymphadenopathy, gum hyperplasia, testes, chloroma

- metabolic effects: fever, anorexia, weight loss, disseminated intravascular coagulation, spontaneous tumour lysis - increased uric acid production -> renal failure

12

Clonal theory of malignancy

- cancers arise from malignant transformation of a single cell
- but clonal hemapoiesis doesnt always lead to malignancy: 4% of people have clonal hemapoiesis, slightly increase risk of developing cancer but something else needs to happen

13

Examples of clonal changes

- repeated identical chromocome abnormalities
- repeated DNA changes and mutations: gene rearrangements
- repeated protein abnormalities: aberrant immunophenotype, light chain restriction

14

Some common leukemia-associated chromosomal translocation

- APL - RARA gene
- AML M2 - RUNX1 gene
- ALL -> MLL gene
- CML and ALL -> ABL gene (t(9;22))
- Burkitt's lymphoma and leukemia - > MYC gene (t(8;14,2,22))

15

Imatinib

- TK inhibitor
- sits in ATP bindign site and stop fusion protein from binding to substrate
- very effective

16

Flow cytometry in CLL

- abberant immonophenocype: express both CD19 (B cell marker) and CD5 (T cell marker), or express neither
- light chain restriction: only one type of light chain - indicates clonal expansion