BLD 424 Exam 2: white blood cells

clonal hematopoiesis definition

expansion of a single clone of stem cell in the bone marrow. The clone has a growth advantage and expands to dominate the stem cell pool

clonal hematopoiesis occurrence

1. can inherit

2. can be due to aging/inflammation

3. disease association: leukemias and lymphoma, heart disease, hypertension

carcinogenesis

mutation of a checkpoint repair protein, signaling, protein or oncogene

signal transduction

The message to initiate division and process to completion has to be transferred from the external cell environment to the nucleus by a series of proteins

cancer results in

1. increased rate of division

2. failure to apoptosis mechanisms

cancer results from mutations (usually acquired) do one of the following

1. proto-oncogene is changed to an oncogene

2. impaired apoptosis - abnormal cells done die

3. inactivation of cancer suppressor gene (p53)

autocrine

1. stimulate excessive cell growth

2. produce growth factors (by mutated cell): cell mutates to produce its own growth factor without normal regulatory control

3. produce defective growth factor receptor: no growth factor required for receptor to modify signal transducers

4. produce defective signal transducers

5. produce transcriptional activators that are stimulated without normal signal trasnducers

mutated transcriptional activators induce resistance to apoptosis

-important in some leukemias

-missing the mechanism to induce or respond to apoptosis

-cells become immortal bc they do not die as they should

cancers like leukemia and lymphoma result from:

acquired genetic mutations in a hematologic stem cell that:

1. give rise to cells that divide without responding to normal regulation

2. cells live beyond normal life span due to failed apoptosis

3. cells are not detected by tumor surveillance mechanisms

cancer initiation is multifactorial, including:

somatic mutations due to:

1. radiation (UV)

2. toxins/pollutants

3. viruses- retroviruses: incorperate DNA into the human genome preferably at protooncogene sites

4. mutated genes can be inherited (BRACA)

multi hit theory

more than one mutation must happen in a cell before it becomes a cancer cell

mutations may be

1. point mutation

2. chromosomal rearrangement

3. gene applification

leukemia

cancer of blood cells resulting from clonal proliferation of hematologic stem cells bearing a mutated gene and resulting in leukocytosis of the affected cells

-affects one or more lymphoid or myeloid cells

pathological features of leukemia

1. predominance overtime of one cell type

2. anemia: pallor and fatigue

3. infection: fever, nightsweats

4. decreased platelets: bruising and bleeding

5. increased inflammatory cytokines: anorexia, cachexia

6. death due to infection or hemorrhage

predominance overtime of one cell type

pathological feature of leukemia

1. expansion of affected cells in bone marrow

-spillover of marrow cells in the blood = leukocytosis

-relative and absolute numbers of affected cell type increased

2. mutated cells expand to other sites of cell production

-lymphadenopathy: lymphatic anemia

-hepatosplenomegally: myeloid leukemia

treatments for leukemia

1. anemia: EPO and transfusions

2. chemotherapy: kill cancer before it kills you

3. leukopenia: g-csf

4. cell cycle regulators

effects of chemotherapy treatment on bone marrow and blood

get anemia, thrombocytopenia, leukopenia

peripheral blood CBC clues to leukemia

1. leukocytosis with blasts in variable numbers (sometimes there is leukopenia)

2. normocytic/normochromic anemia

3. thrombocytopenia (exception is chronic myelocytic leukemia)

bone marrow examination for leukemia

diagnostic but can be inconclusive

1. hypercelullarity: increased cells, decreased fat/yellow marrow

2. elevated myeloid: erythroid ratio (M:E)

-estimate proportions of cells

-calculate M:E

-can predict effects of leukemia and anemia based on M:E

3. affected cell line will predominate

tests for leukemia

1. peripheral blood smear can give clues but is not diagnositic

2. bone marrow examination of tissue is diagnositic but can be inconclusive

3. cytochemical stain

4. immunophenotyping

5. karotyping

6. FISH

lymphoma

malignant proliferation of lymphoid cells in the lymph nodes

hallmark of lymphoma

painless lymphadenopathy

lymphoma diagnostics

1. anemia: ACI, myelophthisic, immuno hemolytic

2. progresses to leukemic stage

3. thrombocytopenia

4. bone marrow analysis

5. diagnostic tissue: enlarged tissue

hodgkins disease

associated with EBV infections: reed sternberg cells

-clonal proliferation of lymphocytes at some stage of development

non hodgkins lymphoma

1. no reed sternberg cell

2. clonal proliferation of lymphocytes representing a stage in lymphocyte proliferation or the antigen response