Hematology, Molecular Basis Of Leukemia And Its Diagnostic Tools

Front 1

what are the three white cell neoplastic disorders we will study in this course?

Back 1

1. leukemias
2. lymphomas
3. myeloproliferative disorders

Front 2

cancers of the blood or bone marrow are called?

Back 2

leukemias

Front 3

a cancer causing overproliferation of progenitor cells in the bone marrow is termed?

Back 3

leukemia

Front 4

what are the two cell lineages which can be effected by a leukemia?

Back 4

1. myeloid
2. lymphoid

Front 5

does this describe acute or chronic leukemia?

Block in differentiation results in accumulation of stem/progenitor cells which eventually fill the bone marrow cavity and spill out into the blood stream as blasts?

Back 5

acute

Front 6

when suppression of normal hematopoietic stem cells occurs, what is the term for the resulting in a decrease of all types of normal blood cells?

Back 6

Pancytopenia

Front 7

why are acute leukemias aslo called clonal disorders?

Back 7

all the abnormal cells came from one original cell thus all have the same characteristic mutations

Front 8

what are the 2 types of acute leukemias?

Back 8

1. Acute lymphoblastic Leukemia (ALL)
2. Acute myeloid leukemia (AML)

Front 9

Is chronic or acute leukemia described below?

No clear blockage of progenitor cell maturation, but there are a heterogeneous collection of mature and immature WBC's in the blood.

Back 9

Chronic leukemia

Front 10

why are chronic leukemias watched very closely even if it appears they are progressing very slowly?

Back 10

they can change into acute leukemia over a very short period of time

Front 11

what are the two classifications of chronic leukemias?

Back 11

1. Chronic myelogenous leukemia (CML)
2. Chronic lymphocytic leukemia (CLL)

Front 12

Cancers of the lymph tissue are called?

Back 12

Lymphomas

Front 13

an over production of lymphoid cells in the lymph nodes, spleen, or other lymphoid organ is known as?

Back 13

lymphoma

Front 14

what are the 2 types of lymphomas?

Back 14

1. Hodgkin's disease
2. Non-Hodgkin Lymphomas (NHL)

Front 15

What is this cell and what white cell neoplastis disorder might cause its formation?

Back 15

Reed-Sternberg Giant Cell caused by Hodgkins lymphoma

Front 16

what are the 3 techniques for typing a lymphoma?

Back 16

1. Morphology
2. Molecular Genetics
3. Immunophenotype determination

Front 17

what typing test for lymphomas relies on determining to B or T cell clonality and chromosomal translocations?

Back 17

Molecular genetics

Front 18

detection of surface membrane antigens (the CD type) is characterized by what technique used to determine the typing of a lymphoma?

Back 18

Immunophenotype determination

Front 19

Cancer of myeloid cells is called?

Back 19

a myeloproliferative disorder

Front 20

an excesss production of granulocytes is called?

Back 20

Chronic myelogenous leukemia (is a myeloproliferative disorder)

Front 21

an excess production of erythrocytes is called?

Back 21

Polycythemia vera (is a myeloproliferative disorder)

Front 22

an excess production of platelets is called?

Back 22

Essential thrombocytopenia or ET (is a myeloproliferative disorder)

Front 23

an excess production of fibroblasts of the bone marrow is called?

Back 23

Agnogenic myeloid metaplasia (AMM) or idiopathic myelofibrosis (is a myeloproliferative disorder)

Front 24

what is a good way to distinguish between a reactive process and a myeloproliferative disorder?

Back 24

myeloproliferative disorders are usually monoclonal where as a reactive process would not be

Front 25

cytogenic abnormalities, marrow hyperplasia or hypermetabolism, and abnormal maturation of WBC's indicate what type of white cell neoplastic disorder?

Back 25

Myeloproliferative disorder

Front 26

what percentage of caners in the U.S. are a type of leukemia?

Back 26

5%

Front 27

what percentage of malignant diseases in children are leukemias?

Back 27

50%

Front 28

what are the 3 common molecular characteristics of leukemias?

Back 28

1. subtractions, additions, translocations on various chromosomes
2. Absent, increased, or decreased cellular proteins
3. Ability to proliferate inside the marrow even when producing faulty copies

Front 29

basic diagnosis of leukemia can only be made when what number of cancer cells is present?

Back 29

10^9 for chronic phase
10^12 for acute phase

Front 30

what is the most common cause of acute and chronic leukemias is which of the following?

1. translocations
2. subtractions
3. additions

Back 30

translocations

Front 31

interchromosomal gene rearrangements are called?

Back 31

translocations

Front 32

what is the translocation found in CML?

Back 32

t(9;22)(Ph1)

Front 33

what is the translocation found in AML?

Back 33

t(8;21)

Front 34

what is the translocation found in APL?

Back 34

t(15;17)

Front 35

what is the translocation found in Burkitt's Lymphoma?

Back 35

t(8;14)

Front 36

what is the abnormal protein resulting in CML?

Back 36

bcr/able

Front 37

what is the abnormal protein resulting in AML?

Back 37

CBF/AML1

Front 38

what is the abnormal protein resulting in APL?

Back 38

RAR-alpha

Front 39

what is the abnormal protein resulting in Burkitt's Lymphoma?

Back 39

Ig/myc

Front 40

what percentage of patients with CML have the t(9;22)(Ph1) translocation?

Back 40

95%

Front 41

describe the effect of the bcr/able protein mutation causes?

Back 41

bcr/abl become fused resulting in a constitutively active abl tyrosin kinase

Front 42

how is CML diagnosed?

Back 42

karyotyping that reveals the presence of the philadelphia chromosome (chromosome 22) which is shorter than it should be

Front 43

describe the pathogenesis of the CBF-AML1 protein mutations that lead to AML?

Back 43

CBF-AML1 normally enhances transcription of hematopoietic genes that are essential for differentiation. In the mutation, ABL1 can bind an additional co-repressor complex which completely stops transcription of the genes responsible for progenitor cell differentiation causing a build up of "blasts"

Front 44

what happens in the inv(16) mutation with CBF/ABL1?

Back 44

CBF is mutated and when it binds to ABL1 they are ejected from the nucleus and cannot enhance transcription of differentiation genes

Front 45

what is RAR?

Back 45

retinoic acid receptor

Front 46

what does vitamin A deficiency cause?

Back 46

abnormal hematopoiesis

Front 47

what is the cure for APL cancer?

Back 47

all-trans retinoic acid (ATRA) because it can induce terminal differentiation in cell lines where RAR has been mutated to form a chimeric RAR

Front 48

what are c-myc genes invloved in?

Back 48

regulation of cell cycle

Front 49

what are IgG genes involved in?

Back 49

code for immunoglobulins

Front 50

describe the pathogenesis of Burkitt's Lymphoma?

Back 50

The promotor IgG gene gets placed next to the c-myc gene resulting in a oncogene which causes increased B-cell proliferation

Front 51

what are the 3 types of changes that are seen in the HL-60 cancer cell model?

Back 51

1. A growth factor receptor becomes constitutively activated
2. A tumor suppressor gene is deleted
3. A oncogene is overactive

Front 52

What are the structures indicated by the arrows?

Back 52

Auer Rods seen in AML

Front 53

what are 2 examples of enzyme assays that can be used to diagnose leukemia?

Back 53

1. Myeloperoxidase activity (is it present?)
2. Alkaline phosphatase activity (low in leukemia)

Front 54

what are the two tools which can be used for genetic analysis in leukemia?

Back 54

1. FISH
2. PCR

Front 55

Describe how FISH analysis works?

Back 55

Probes for specific sequences of DNA such as BCR and ABL1 can be created to fluoresce specific colors when they are bound to target sites. If the target genes are together such as BCR/ABL1 then there colors will merge to make a new color

Front 56

what stage of mitosis should cells be in for use of FISH?

Back 56

metaphase

Front 57

what stage of mitosis can lead to false positives?

Back 57

interphase because around 4% of cells show an overlap of BCR/ABL1 in interphase

Front 58

how is PCR used to find cancerous cells?

Back 58

primers are created which will bind to specific points of DNA near protoncogenes. When these genes are brought together the polymerase reaction is able to occure and the cancerous DNA will be amplified so that it can be identified. If no cancerous cells are present then PCR reaction is not succesful.

Front 59

Describe the technique of flow cytometry?

Back 59

Monoclonal antibodies to specific CD (cluster differentiation = glycoprotein fingerprint of luekocyte) that are labeled with a flourescent tag. Different leukocytes or mutated leukocytes can be identified by this method

Front 60

what key factor allows flow cytometery to identify cells in varrying stages of development?

Back 60

as cells develope their CD fingerprint changes thus not only do cells of differing lineages have unique CD fingerprints, but also cells within the same lineage with differing degrees of maturity

Front 61

what is the important CD domain which must be evaluated before a marrow transplant?

Back 61

the MHC domain

Front 62

what is the role of the MHC domain on cells?

Back 62

to identify the cell as belonging to the organism

Front 63

what are the two types of MHC?

Back 63

Class I and Class II

Front 64

how many MHC class I does each human have?

Back 64

6

Front 65

how many MHC class II does each human have?

Back 65

8

Front 66

which cells in the body have MHC class I?

Back 66

all

Front 67

which cells in the body have MHC class II

Back 67

APC's

Front 68

what T cells recognize MHC class I and destroy non-self cells?

Back 68

Cytotoxic killer T cells

Front 69

which T cells recognize MHC class II?

Back 69

helper-T-cells

Front 70

what is the target for antibodies conjugated with drugs or radioactive isotopes in AML?

Back 70

CD33

Front 71

what is the target of the engineered chimeric antibody against NHL?

Back 71

CD21

Front 72

what superfamily to GM-CSF, IL-3 and IL-5 belong to?

Back 72

cytokine superfamily

Front 73

describe the GM-CSF receptor?

Back 73

an alpha and beta subunit which when complexed allows GM-CSF to bind to its receptor and transduce a signal

Front 74

the signal tranduced by binding og GM-CSF to its receptor can start which 3 molecular intracellular pathways?

Back 74

1. Ras/MAPk
2. JAK-STAT
3. PI3k/P70S6k

Front 75

Ras/MAPk pathway results in what?

Back 75

initiation of gene transcription by the activation of c-fos, c-jun, and c-myc

Front 76

the JAK/STAT pathway results in what?

Back 76

proliferation and differentiation

Front 77

the PI3k/P70S6k pathway results in what?

Back 77

protein synthesis leading to cell growth

Front 78

which of the singal tranduction pathways are associated with leukemia and what type?

Back 78

1. Ras and Abl are associated with CML [t(9;22)]
2. Myc malfunction is associated with Burkitt's Lymphoma [t(8;14)]

Front 79

Explain the role of Ras in developing cancer?

Back 79

it normally sends out a proliferative signal when grwoth factors are present. In its mutated form in is on constantly.

Front 80

what is the new treatment being investigated to treat Ras mediated cancer?

Back 80

drugs blocking the enzyme farnesyl transferase which activates Ras thus stopping ras's ability to cause cell proliferation