INTRODUCTION TO HEMATOLOGIC NEOPLASM Flashcards
1
Q
from abnormal growth of cells of the hematopoietic system
first human cancers in which a consistent genetic defect was identified
leukemias, lymphomas, and myelodysplastic syndromes
A
Hematologic neoplasms
2
Q
- described a consistent shortened chromosome in seven patients with CML.
- “Philadelphia chromosome”
A
1960 Nowell and Hungerford
3
Q
Chromosome in CML.
A
- “Philadelphia chromosome”
4
Q
- reported the t(9;22) translocation in CML
A
1973 Rowley
6
Q
- proliferate in lymph nodes and other lymphoid organs and tissues
A
Lymphomas
7
Q
- reported the t(8;14) translocation in Burkitt lymphoma
A
1982 Taub and colleagues
8
Q
A
9
Q
- solid tumors of lymphoid cells
originate in the lymphatic system
A
Lymphomas
10
Q
- lymphoid and myeloid lineages
- acute (precursor cell) and chronic (mature cell)
A
Leukemias
11
Q
Categories of leukemia
A
Acute
Chronic
12
Q
- accumulation of precursor hematopoietic cells of a specific lineage (bone marrow and peripheral blood) - “maturation arrest”
A
Acute
13
Q
• sudden, rapid, and fatal in weeks or months if left untreated.
- WBC count is variable
A
Acute
14
Q
- proliferation and accumulation of mature and maturing cells of a specific lineage
A
Chronic
15
Q
- insidious and slower, with a longer survival compared with acute leukemia.
- WBC count is usually elevated
A
Chronic
16
Q
• Hematopoietic cells in BM > replaced by leukemia cells > affects normal BM function
A
Untreated leukemias
17
Q
Untreated leukemias
- Bleeding ‹_____
• Fever ‹______
‹ Fatigue <______
A
thrombocytopenia
neutropenia-induced infection
decreased hemoglobin concentration
18
Q
Predominant cell type
A
C
A
Precursor cell or blast
Mature
19
Q
Onset
A
C
A
Sudden
Insidious
20
Q
Symptoms at presentation
A
C
A
Fever (as a result of neutropenia-induced infection)
Mucocutaneous blending (as a result of thrombocytopenia)
Fatigue (as a result of anemia)
Variable, nonspecific;
some asymptomatic
21
Q
White blood cell count
A
C
A
Variable
Increased
22
Q
Progression without treatment
A
C
A
Rapid; wetks to months
Slower, months to years
23
Q
Acite lymohoid leukemia
ALL - common in…
A
young children
24
Q
• Chronic lynphoid leukemia-CLL and myelodysplastic syndrome - common in…
A
older adults
25
Q
/ induce genetic changes › malignant phenotype.
A
Environmental toxins
26
Exposure
(2) > ***lead to hematologic neoplasms***
(1) > ***induce DNA damage in hematopoletic cells***
Radiation ( atomic explosions) and Organic solvents
Alkylating agents (chemotherapy)
27
- ability to insert into host cell genomes
- genetic and epigenetic changes
Viruses
28
- produce oncoproteins that
- interfere with normal cell processes
Viruses
29
- invades CD41 lymphocytes > adult T cell leukemia/lymphoma
HTLV-1
30
HTLV-1
- invades_____ > adult T cell leukemia/lymphoma
CD41 lymphocytes
31
- invades mainly B lymphocytes > Burkitt and other non-Hodgkin lymphomas and in a subset of classic Hodgkin lymphoma.
Epstein-Barr virus
32
33
Epstein-Barr virus
- invades mainly_____ > Burkitt and other non-Hodgkin lymphomas and in a subset of classic Hodgkin lymphoma.
B lymphocytes
34
- immunosuppression > risk of non-Hodgkin lymphoma
HIV-1
35
36
- mutations in ATM
‹ Ataxia telangiectasia
37
- mutation in TP53
~ Li-Fraumeni syndrome
38
- mutation in genes for telomere maintenance
‹ Dyskeratosis congenita
39
- mutation in one of the FA genes needed for DNA repair
Fanconi anemia
40
"molecular policeman" is a nuclear transcription factor that promotes cell cycle arrest and apoptosis
TP53
41
- devised in the 1970s and 1980s
- based largely on ***morphologic characteristics***
- ***routine histologic stain*** > distinguish ***lymphoid neoplasms from myeloid neoplasms***
FAB Classification
42
Published in 2001 and updated in 2008 and 2016 (______\)
> clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics
Society for Hematopathology and the European Association for Haematopathology
43
Cellular Processes perturbed in Hematologic Neoplasm
• chromosomal rearrangement (such as translocation or inversion),
• gain or loss of chromosomes (aneuploidy)
• total or partial gene deletion
• point mutation
• Insertion
• gene duplication/amplification
44
• "initiation and maintenance of leukemia"
• hematopoietic cell - accumulates multiple, independent mutations or ***"multihits"***
• affect cellular pathways > malignant clone
LEUKEMOGENESIS
45
LEUKEMOGENESIS ЕХСЕРТ
_______
> one genetic mutation, the
> t(9;22) with fusion of the BCR-ABL1 genes
CML
46
Examples of Cell Proteins Altered in Hematologic Neoplasms
Cell cycle regulatory proteins
Nuclear transcription factors
Checkpoint control proteins
Pro- and anti-apoptotic proteins
DNA repair proteins
Signal transduction proteins
Growth factor receptors
47
Results of Disruption
• Uncontrolled proliferation
• Loss of DNA repair capability and cell cycle control
• Block in differentiation
• Continued cell survival and inhibition of apoptosis
48
49
- mutation that codes for signal transduction proteins or growth factor receptors
- activation without stimulus and without ability to suppress
Uncontrolled proliferation
50
- inactivating mutation or deletion of genes coding for DNA repair proteins
- cell cycle proteins that regulate the cell cycle
- checkpoint control proteins that arrest the cell cycle when DNA is damaged
• Loss of DNA repair capability and cell cycle control
51
- mutation in genes coding for nuclear transcription factors or aberrant changes in their epigenetic regulation
- maturation arrest or dysplastic changes.
• Block in differentiation
52
- mutation or deletion of genes coding for propoptotic and other related proteins
- persistence of leukemic stem cells
• Continued cell survival and inhibition of apoptosis
53
-______ is essential to contain and control the massive cell expansion that occurs in the hematopoietic system during times of stress, infection, or hemorrhage
apoptosis
54
Examples of Epigenetic
Mechanisms That Control Gene Expression
DNA methylation
Histone acetylation
microRNAs
(miRNAs)
55
Hypermethylation of CpG islands in gene promoters and other noncoding DNA regions by DNA methyltransferases prevents gene transcription and expression.
DNA methylation
56
Histone acetyltransferases keep DNA chromatin in an open configuration so transcription can accur.
Histone deacetylases (HDACs) keep DNA chromatin in a closed configuration so genes are unavailable for transcription, replication, and repair.
Histone acetylation
57
miRNAs (small 22 nucleotide RNA segments) inhibit gene expression by specifically binding to targeted mINA transcripts, blocking their translation to protein, and causing their destablization and degradation.
microRNAs (miRNAs)
58
- originally were identified in tumor-forming retroviruses
- derived from normal human cellular homologues called protooncogenes
Oncogenes
59
Oncogenes
- originally were identified in tumor-forming retroviruses
- derived from normal human cellular homologues called______
protooncogenes
60
Protooncogenes are important in:
signaling pathways
cell proliferation
cell differentiation
Apoptosis
61
Protooncogenes
- Mutations converts it to_____ with leukemogenic potential
- Dominant disorders
oncogene
62
Mutations that Activate Protooncogenes
_________
- alterations ***involve a structural change*** to the protooncogene and production of an abnormal protein product.
***translocation t(9;22)*** forming the BCR-ABL1 fusion gene in CML and in some cases of acute lymphoblastic leukemia.
Qualitative
63
Mutations that Activate Protooncogenes
- ***overexpression of a normal protooncogene***
B-lymphoid neoplasms - ***translocation*** next to the promoter of the Ig heavy chain (IGH) on chromosome 14.
Quantitative
64
code for proteins that protect cells from malignant transformation.
slow down cell division or promote apoptosis.
Tumor Suppressor Genes
65
- promote malignant transformation when they are inactivated or deleted
tumor suppressor genes
66
67
Tummor suppressor gene
>____ in Li-Fraumeni syndrome
TP53
68
- involved in hematologic neoplasms.
- Genetic instability and increased mutation rates > malignant transformation.
DNA Repair Genes
69
>_______ gene, FA, which is important for maintaining genomic stability in hematopoietic tissues
Fanconi anemia
70
General Categories of Therapy for Hematologic Neoplasms
Chemotherapy
Radiation Therapy
Supportive Therapy
Targeted Therapy
Hematopoietic stem cell transplantation
71
Cell cycle effects: phase specific or phase nonspecific agents
Biochemical mode of action: alkylating agents, plant alkaloids, antimetabo-lites, antitumor antibiotics, glucocorticoids
Chemotherapy
72
Supportive therapy
Eg
Growth factors and cytokines
73
Targeted therapy
(3)
Targeted molecular therapy
Immunotherapy
Cellular therapy
74
Hematopoietic stem cell transplantation
(3)
Syngeneic
Allogeneic
Autologous
75
3 phases: induction, consolidation, and maintenance
Chemotherapy
76
77
- oral or parenteral treatment - possess antitumor properties
Chemotherapy
78
Chemotherapy
3 phases:
induction, consolidation, and maintenance
79
> decrease the tumor burden and achieve remission
Chemotherapy
80
Chemotherapy
> Types of Remission
______: normocellular bone marrow, recovery of blood cell counts, and no microscopic evidence of leukemia cells
/______: absence of the cytogenetic defect determined by karyotyping methods
/______: absence of leukemia cell nucleic acid sequences
Hematologic
Cytogenetic
Molecular
81
Affected during radiotherapy
hematopoietic system gastrointestinal tract v skin
82
- producing unstable ions that damage DNA
- cause instant or delayed death of cells
Radiation Therapy
83
Supportive therapy
- rapidly expand the number of mature neutrophils
• G-CSF and GM-CSF
84
Supportive therapy
- rapidly expand the number of mature neutrophils
• G-CSF and GM-CSF
85
Supportive therapy
- RBC formation and recombinant forms are administered to cancer patients with anemia
• ЕРО
86
- act specifically on malignant cells and leave normal cells untouched.
- the dream is to move away from nonspecific therapies
Targeted Therapy
87
is now the first-line treatment for chronic-phase CML
- long-term remissions of 10 years and longer
Imatinib
88
- high efficacy in patients with high-risk hematologic neoplasms.
Cellular therapy
89
- also used in hematologic neoplasms to reverse epigenetic silencing of gene
Epigenetic therapies
90
Hematopoietic Stem Cell Transplantation
Bone marrow
Peripheral blood
Umbilical cord blood
91
- posterior iliac crests
- general or regional anesthesia
• Bone marrow
92
- less invasive in that they are
- harvested by pheresis after mobilization out of bone marrow by cytokines and chemokines
• Peripheral blood
93
94
- umbilical vein after the infant is delivered
- cord is clamped and cut
Umbilical cord blood (UCB)
95
- patient's own marrow or peripheral blood stem cells
• Autologous
96
- HLA-identical sibling or
- HLA-matched unrelated donor
• Allogeneic
97
- identical twin
Syngeneic
98
99
