1/6 Molecular Basis of Hematologic Malignancy - Corbett Flashcards
steps in malignant transformation
- non-lethal genetic damage
- acquired (chemicals, radiation, viruses)
- inherited
- damage disruption of key regulatory genes
- growth promoters (proto-oncogenes)
- growth suppressors (tumor suppressor genes)
- regulators of programmed cell death
- genome guardians
balanced reciprocal translocation
why are lymphoid cells common targets of gene rearrangement?
single breaks occur in two chromosomes, switch spots
often leads to…
- overexpression of gene product
- abnormal function
lymphoid cells purposely make DNA breaks
- normal antigen receptor recombo (B and T cell progenitors)
- class switch recombo (antigen-stimulated mature B cells)
oncogenes
proto-oncogenes
oncogenes: genes that promote autonomous cell growth in cancer cells
- single gene mutation is enough to promote unreg’d growth
proto-oncogenes: unmutated cellular counterparts of oncogenes, including…
- transcription factors
- growth regulatory proteins
- cell survival proteins
- cell-cell and cell-ECM interaction proteins
5 ways to create sustained growth signals
- receptor activation
- non-receptor tyrosine kinases
- downstream signal-transducing proteins
- nuclear transcription factors
- cell cycle proteins
- cyclins
- cyclin-dependent kinases
myeloproliferative disorders
mast cell
RBC
platelet
eosinophil
neutrophil
monocyte
receptor-assoc or cytoplasmic signaling molecules
activation of nonreceptor Tyr kinases
polycythemia vera mutation
JAKV617F
essential thrombocytosis
primary myelofibrosis
role of c-Abl
constitutive activation of c-Abl
comparison of c-Abl and Bcr-Abl
c-Abl is a tyrosine kinase
- promotes growth and survival
- helps regulate DNA damage repair response
balanced translocation between ch9 (abl) and ch22 (bcr) produces Philadelphia chromosome (altered ch22) containing bcr-abl
- c-Abl gains a domain from BCR that facilitates dimerization → constitutive kinase activity
comparison:
- Bcr-Abl is constitutively active
- Bcr-Abl is trapped in cytoplasm
RAS-RAF PATHWAY
gain of fx point mutation on ras → constitutive activation → signalling to MAP kinase to enhance proliferation
ex. hairy cell leukemia: 100% have a BRAF mutation
nuclear transcription factors
c-MYC
cMYC is an imp activator of transcription (among other things)
generally, promotes cell growth
Burkitt lymphoma is associated with overexpression of c-myc
Burkitt lymphoma
connection to transcriptional activation
tumor of mature B cells
3 forms:
- endemic Burkitt lymphoma (eBL): jaw and facial bone (orbit) involvement in over 50% of cases
- sporadic Burkitt lymphoma (sBL): ileocecal or peritoneal tumors that cause swelling and pain
- HIV-associated
all assocaited with c-myc translocation
- classic t(8:14) translocation of c-myc such that it ends up adjacent for IgH promoter on chr14!
as a result, IgH promoter acts on c-myc → v high levels of c-myc seen
BCL6
associated illness
transcriptional repressor in germinal center B cells
- lots of fx, but key: inhibition of response to genotoxic stress (p53, ATR)
sooo if BCL6 is active all the time, then normal surveillance mechanisms are shut down all the time = BAD
overexpression of BCL6 associated with diffuse large B cell lymphoma
- occurs one of two ways:
- translocation placing BCL6 under control of new promoter (30%)
- small deletions or somatic point mutations in BCL6 regulatory region (70%)
acute promeylocytic leukemia
associated with…
assoc with transcriptional repressor
balanced 15:17 translocation
- resulting fusion protein blocks retinoic acid-induced myeloid differentiation AND enhanced self-renewal
cell cycle control
roles of cyclins, cylin-dependent kinases, CDK inhibitors
and connection to unchecked growth
loss of cell cycle control is central to malignant transformation
defects in G1/S phase checkpoint are associated with unchecked growth
two classes of cancer mutations:
-
gain of function mutations in oncogenes
- D cyclin genes
- cyclin-dependent kinase 4 (CDK4)
-
loss of function mutations in tumor suppressor genes
- cyclin dep kinase inhibitor (CDKN2A)
- Retinoblastoma protein 1 (Rb1)
mantle cell lymphoma
overexpression of cyclin D1
- 11:14 translocation involving…
- IgH locus on chr14
- cyclin D1 locus on chr11
upreg of cyclin D1 promotes G1→S phase transition
loss of cell cycle regulation
gain of fx mutations
- increased CDK4/cyclinD activity
*
evasion of cell death
apoptotic pathways
accumulation of neoplastic cells can result from mutation in genes that regulate apoptosis
- mitochondrial (intrinsic) pathway
- cell injury → Bcl2 sensors → Bcl2 effectors (Bax, Bak) hit mitochondria and promote pore formation→ mito releases cytochrome c, APAF1 and other pro apoptotic proteins → initator caspases → executioner caspases
- regulators (Bcl2, Bcl-xl) are antiapoptotic
- Bcl2 binds Bax/Bak to prevent pore formation
- Bid, Bad, PUMA promote apoptosis by binding Bcl2 and keeping Bax/Bak free
- death receptor (extrinsic) pathway
how do tumor cells evade death?
- loss of p53 reduces pro-apoptotic Bax/Bak
- upreg of anti-apoptotic BCL2
- loss of APAF1
- upreg of inhibitors of apoptosis (IAP)
BCL2 and cancer
Bcl2 has well established role in protecting malignant lymphioid cells from apoptosis
follicular lymphoma arises from germinal center B cells
90% carry characteristic 14:18 translocation
- results in overabundance of BCL2 protein (necessary but not sufficient for malignant transformation)
- lymphocytes are protected from apoptosis as a result
- see lymphadenopathy and marrow infiltration as numbers increase
key genes/mutations and diseases
key PROTEINS and translocations for:
diffuse large B cell lymphoma
Burkitt lymphoma
mantle cell lymphoma
follicular lymphoma
CHROMOSOME 14
disease and translocation associated with:
BCL6
CCND1/CyclinD1
cMYC
BCL2
