Lecture 12: Lymphoma Biology

Question 1

Diffuse large B-cell lymphoma (DLBL)

Answer 1

most common

Question 2

CD79A/B mutations and LYN kinase

Answer 2

LYN kinase normally binds to CD79 ITAMS and dephosphorylate CD79 to turn off signal

mutant CD79 cannot bind to LYN kinase

cannot be turned off by LYN kinase

Question 3

Bruton’s Tyrosine Kinase (BTK)

Answer 3

leads to oncogenic pro-survival pathway through activation of NFkB

Question 4

Ibrutinib

Answer 4

a small molecule covalent BTK inhibitor

covalent binding: slower off rate, require less concentration of drug for inhibition

binds to cysteine 481 ATP binding pocket

Question 5

CBM heteromer and CARD11 mutation

Answer 5

activates NFkB downstream of BTK

mutant CARD11 spontaneously activates NFkB (pro survival) independent of signalling from BCR through BTK

lymphomas driven by CARD11 mutation are resistant to Ibrutinib

Question 6

MYD88 mutations

Answer 6

part of innate immune response

recruit IRAK1, 4 in response to IL-1R or TLR activation

mutant L265P MYD88 can recruit kinase IRAK1 and 4 without receptor activation

leads to downstream activation of NFkB, p38 and interferon

Question 7

PI3K isoforms

Answer 7

tissue specific

PI3K delta specific inhibitor (leukocytes) can alleviate off tumor effects of pan-PI3K inhibitors

Question 8

Idelalisib

Answer 8

inhibitor of PI3K delta (lymphocytes specific) isoform

Question 9

Mechanism of resistance to Idelalisib in Mantle Cell lymphoma (MCL)

Answer 9

usually only p110 delta is predominant

after Idelalisib treatment p110 alpha isoform expression increased

disease is no longer dependent on the effect of p110 delta isoform

Question 10

Lymphoma tumor microenvironment

Answer 10

different type of tumors and different degree of microenvironment involvement

dictate by the types of soluble factors (cytokines and chemokines) released into surrounding tissue

acts as attractants for other cell types

Question 11

3 steps in cancer immunity cycle

Answer 11

1. tumor cell death results in release of tumor antigens that are processed by dendritic cells
2. dendritic cells migrate to lymph nodes and prime naive T-cells to have anti cancer activity
3. Activated T cells travel and infiltrate tumor and kill cancer cells

Question 12

Immune checkpoint deactivation by PDL1

Answer 12

PDL1 on tumor cells bind to PD1 on T cells to deactivate T-cell function

Question 13

Immune surveillance

Answer 13

The ability that immune system can detect and destroy cancer or pre-cancerous cells before that can form an established tumor

Question 14

Immune evasion

Answer 14

the ability of cancer cells to shutdown or override the immune system

Question 15

Immune checkpoints PD-1 and CTLA4

Answer 15

upon binding PD-1 and CTLA4 transmit negative regulatory signals and suppress T-cell anti-tumor activity

Question 16

9P24 amplification in Hodgkin Lymphoma

Answer 16

PD-L1 and PD-L2 genes located in close proximity to each other on chromosome 9P24

increase JAK2 level and drive PD-L1 expression through JAK/STAT signalling

Question 17

Potential downside of using therapeutic antibodies

Answer 17

limited tumor penetration

lack of oral bioavailability

immunogenicity

cumbersome production