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M2 Heme/Onc > 1/6 Molecular Basis of Hematologic Malignancy - Corbett > Flashcards

1/6 Molecular Basis of Hematologic Malignancy - Corbett Flashcards

1
Q

steps in malignant transformation

A
  1. non-lethal genetic damage
  • acquired (chemicals, radiation, viruses)
  • inherited
  1. damage disruption of key regulatory genes
  • growth promoters (proto-oncogenes)
  • growth suppressors (tumor suppressor genes)
  • regulators of programmed cell death
  • genome guardians
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2
Q

balanced reciprocal translocation

why are lymphoid cells common targets of gene rearrangement?

A

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)
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3
Q

oncogenes

proto-oncogenes

A

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
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4
Q

5 ways to create sustained growth signals

A
  1. receptor activation
  2. non-receptor tyrosine kinases
  3. downstream signal-transducing proteins
  4. nuclear transcription factors
  5. cell cycle proteins
    • cyclins
    • cyclin-dependent kinases
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5
Q

myeloproliferative disorders

mast cell

RBC

platelet

eosinophil

neutrophil

monocyte

A
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6
Q

receptor-assoc or cytoplasmic signaling molecules

A

activation of nonreceptor Tyr kinases

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7
Q

polycythemia vera mutation

A

JAKV617F

essential thrombocytosis

primary myelofibrosis

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8
Q

role of c-Abl

constitutive activation of c-Abl

comparison of c-Abl and Bcr-Abl

A

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
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9
Q

RAS-RAF PATHWAY

A

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

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10
Q

nuclear transcription factors

c-MYC

A

cMYC is an imp activator of transcription (among other things)

generally, promotes cell growth

Burkitt lymphoma is associated with overexpression of c-myc

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11
Q

Burkitt lymphoma

connection to transcriptional activation

A

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

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12
Q

BCL6

associated illness

A

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%)
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13
Q

acute promeylocytic leukemia

associated with…

A

assoc with transcriptional repressor

balanced 15:17 translocation

  • resulting fusion protein blocks retinoic acid-induced myeloid differentiation AND enhanced self-renewal
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14
Q

cell cycle control

roles of cyclins, cylin-dependent kinases, CDK inhibitors

and connection to unchecked growth

A

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:

  1. gain of function mutations in oncogenes
    • D cyclin genes
    • cyclin-dependent kinase 4 (CDK4)
  2. loss of function mutations in tumor suppressor genes
    • cyclin dep kinase inhibitor (CDKN2A)
    • Retinoblastoma protein 1 (Rb1)
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15
Q

mantle cell lymphoma

A

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

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16
Q

loss of cell cycle regulation

A

gain of fx mutations

  • increased CDK4/cyclinD activity
    *
17
Q

evasion of cell death

apoptotic pathways

A

accumulation of neoplastic cells can result from mutation in genes that regulate apoptosis

  1. 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
  2. death receptor (extrinsic) pathway
18
Q

how do tumor cells evade death?

A
  1. loss of p53 reduces pro-apoptotic Bax/Bak
  2. upreg of anti-apoptotic BCL2
  3. loss of APAF1
  4. upreg of inhibitors of apoptosis (IAP)
19
Q

BCL2 and cancer

A

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
20
Q

key genes/mutations and diseases

A
21
Q

key PROTEINS and translocations for:

diffuse large B cell lymphoma

Burkitt lymphoma

mantle cell lymphoma

follicular lymphoma

A

CHROMOSOME 14

22
Q

disease and translocation associated with:

BCL6

CCND1/CyclinD1

cMYC

BCL2

A

M2 Heme/Onc (16 decks)

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