1How are hematologic malignancies acquired?
mostly acquired genetic diseases (SOMATIC mutations)
2What are some examples of hematologic malignancies?
leukemias
lymphoma
myelodysplasia (MDS)
3What happens in hematologic malignancies (general)?
uncontrolled proliferation of hematopoietic cells
mutations/ deletions of key genes in hematopoiesis
4What does hematologic malignancies affect?
mostly systemic
able to infiltrate lymphoid tissues and lymph nodes
5What are the 4 kinds of leukemias?
acute, chronic, lymphoid, myeloid
6What are the general symptoms of leukemias?
bleeding, infection,
fever, fatigue
7What is unknown (direct) cause leukemia often associated with?
environmental toxins, viruses, radiation,
HIV immunosuppression, chemotherapy drugs
8What are some syndromes that can lead to leukemias?
cancer predisposition syndrome
(hereditable germline mutations)
congenital BM failure (FA,DC),
Li Fraumeni (TP53 mut)
AT (ATM mut)
Down syndrome
9What are the BM failures that can lead to leukemia?
Fanconi anemia (FA),
Dyskeratosis congenital (DC)
10How does FA and DC lead to leukemia?
genome instability leads to gene mutations
11How does TP53 lead to leukemia?
TP53 is suppressor protein
12How does AT lead to leukemia?
controls cell proliferation
13What are the 2 kinds of classification schemes for hematologic malignancies?
FAB (acute leukemias)
WHO (2016)
14What is the FAB (French-American-British) classification scheme for acute leukemias?
heavily dependent on cell morph and cytochemistry to distinguish lymphoid from myeloid
AML: M1-M7
15How does the WHO 2016 update classify hematologic malignancies?
updated often by expert panel
combines clinical picture, cell morph, cytogenetics, immunophenotyping, & molecular genetics
16What are the kind of gene mutations that lead to pathogenesis of hematologic malignancies?
deletion, insertion, chromosomal alterations, gene duplication, pt mutations
17What are the cellular processes that lead to pathogenesis of hematologic malignancies?
cell cycle, DNA repair,
Cytokines and GF signaling, apoptosis, signal transduction
18What does P53 affect?
cell cycle arrest (checkpoints)
DNA repair
Senescence
Apoptosis
19What are the epigenetic mechanisms of hematologic malignancies at cellular and molecular levels?
control gene expression (genes are good, expression changes)
heritable (gene seq doesn’t change)
aberrant epigenetic mech in hematopoiesis can maintain neoplasia
20What are the main mechanisms of the epigenetic hematologic malignancies?
1. DNA methylation
2. histone acetylation
3. micro-RNA (miRNA)
21What are some known epigenetic changes?
AML: T(8;21) → RUNX1/ RUNX1T1
PML: T(15;17) → RARA/ PML
22What is a protooncogene?
normal gene, important for cell physiology in:
signaling pathways,
cell proliferation,
cell differentiation,
apoptosis
23What happens if protooncogenes are mutated?
becomes oncogenes leukemogenic
24What generally happens if protooncogenes are mutated?
Oncogenes: leukemogenic
constitutive activation
(GOF: gain of function)
25What oncogenes are present in hematologic neoplasms?
1. signal transducers (tyrosine kinases)
2. growth factor receptors
3. transcription factors
26What kind of hereditary pattern are oncogene mutations?
autosomal dominant (only 1 copy needed to continue phenotype)
27What are qualitative oncogenes?
(affects structure)
Ph in CML, JAK2 in PV,
FLT3-ITD in AML
28What are quantitative oncogenes?
overexpression of normal protooncogene
ex. IGH translocation: BCL2 in t(14;18),
CCND1 in t(11;14)
29What are the 3 kinds of oncogene mutations? (general)
qualitative
quantitative
gene amplification
30What happens in BCL2?
anti-apoptotic protein; blocks apoptosis
31What is CCND1?
cycline D1: induces cell cycle
32What are the general functions of tumor suppressor gene?
protects the cells/ genome
inhibit cell division (proliferation) and induce apoptosis
33What happens if the tumor suppressor gene is inactivated/ deleted?
promote malignant transformation
34What is the inheritance pattern of tumor suppressor genes?
autosomal recessive (needs 2 alleles, homozygous)
35What happens if tumor suppressor gene is inactivation/ deletion?
LOF: loss of function,
2 hit mechanism (?)
36What is the best example of tumor suppressor gene inactivation/deletion?
TP53 Li-Fraumeni syndrome
37What is the purpose of DNA repair genes?
responsible for genome stability
38What happens when DNA repair genes are mutated?
very instable genome, high rate of mutations
39What is an example of DNA repair gene mutations?
Fanconi anemia
40What kind of therapies are used to target hematologic malignancies?
chemotherapy
radiation, supportive, targeted,
hematopoietic stem cell transplantation
41What is the purpose of chemotherapy?
cell cycle inhibitors
42What is the biochemical mode of action in chemotherapy?
alkylating agents, plant alkaloids, antimetabolites,
antitumor antibiotics, glucocorticoids
43What does supportive therapy target?
growth factors and cytokines (to help produce RBC, platelets, etc)
44What is the purpose of targeted therapy?
target specific pathway/ receptor on cell
45What are the 2 kinds of targeted therapy?
immunotherapy (help immune get rid of tumor)
cellular therapy (NK cells kill leukemia)
46What are the 3 kinds of hematopoietic stem cell transplantations?
syngeneic (twin, same gene)
allogeneic (donor)
autologous (self)