A12&A13 - Tumours of the immune system

What are the four key principles of B-cell neoplasia?

• Many B-cell neoplasms retain properties of their normal cell counterparts

• Oncogenic lesions in DNA are an inevitable consequence of genetic recombination/mutation in B-cells

• Oncogenic lesions in B-cell lymphomas alter key aspects of B-cell biology

  • E.g. Proliferation, differentiation, survival and interactions

• Many B-cell lymphomas require antigen receptor signalling, either through cognate antigen or otherwise

What are examples of primary lymphoid tissues?

Bone marrow and thymus

What are examples of secondary lymphoid tissues?

Lymph nodes, spleen and MALTs

What are examples of tertiary lymphoid tissues?

Skin, GI tract and blood

What are risk factors and causes of lymphoid tumours?

• Chance occurrence due to normal lymphocyte physiology (e.g. B-cells)

• Oncogenic viruses

• Immunodeficiency

• Chronic immune stimulation

• Mutagenic agents

What four traits define each type of abnormal lymphoid growth?

• Normal cell counterpart

• Somatic genetic alterations

• Constitutional genetics

• Host immune system/tumour microenvironment

  • Where in the body the tumour occurs

T-cell lymphomas are far more frequent than B-cell ones. True or False?

False.

B-cell lymphomas are far more frequent than T-cell lymphomas.

What treatments can be given for lymphomas?

• Localised radiotherapy

• Single/multiagent (immuno)chemotherapy

• Bone marrow/stem cell transplant

• Novel targeted agents

  • Small molecule enzyme inhibitors

  • Immune checkpoint inhibitors

What are the steps of B-cell differentiation and maturation?

• B-cell precursor undergoes V-region gene recombination

• If a functional, non-self reactive BCR is formed the Naïve B-cell enters the dark zone in a lymph node

• B-cell undergoes clonal expansion and somatic hypermutation of their BCR

  • B-cell may also undergo class switching if a T-cell gives specific signals

• B-cell then differentiates into plasma cell or memory cell

What does Lymphoblastic Lymphoma develop from?

Develop from precursor B-cells

What are key characteristics of Lymphoblastic Lymphoma?

• Increased expression of Terminal deoxynucleotidyl transferase (TdT+)

  • DNA polymerase

• Decreased expression of surface immunoglobulins (sIg-)

What does Mantle Cell Lymphoma develop from?

Develops from unmutated, unswitched Naïve B-cells

What are key characteristics of Mantle Cell Lymphoma?

• Increased expression of IgD (IgD+)

• Decreased expression of CD10/BCL6 (CD10/BCL6-)

What does Follicular Lymphoma develop from?

Develops from mutating B-cells which may/may not be class switched

What are key characteristics of Follicular Lymphoma?

• Increased expression of CD10/BCL6 (CD10/BCL6+)

What does Myeloma develop from?

Develops from mutated, class switched plasma cells

What does MALT lymphoma develop from?

Develops from mutating, switched memory cells

What are key characteristics of MALT lymphoma?

• Decreased expression of IgD (IgD-)

• Decreased expression of CD10/BCL6 (CD10/BCL6-)

What are the two main types of diffuse large B-cell lymphomas?

• Germinal-centre B-cell like

• Activated B-cell like

What are key characteristics of Germinal-centre B-cell like lymphomas?

• Highly mutated Immunoglobulin Heavy Chain (IGH)

• Increased expression of:

  • CD10

  • BCL6

  • LMO2

  • JAW1

  • A-MYB

What are key characteristics of Activated B-cell like lymphomas?

• Mutated IGH

• Increased expression of:

  • IRF4

  • IGHM

  • Cyclin D2

  • CD44

  • FOXP1

What are small copy number changes in relation to genetics?

• Breaks in chromosome resulting in deleted genetic information

• Genetic information may also be duplicated in the chromosome

What are chromosome translocations?

Part of chromosome A translocating to chromosome B while part of chromosome B translocate to chromosome A

Chromosome ‘crossing over’

What is a missense mutation?

Replacement of a nucleotide which results in a different amino acid being encoded.

What is a nonsense mutation?

Replacement of a nucleotide which results in a STOP codon being encoded. This causes a truncated protein to be produced.

What is an insertion mutation?

Insertion of a nucleotide which results in a frameshift. This will likely cause production of a non-functional protein

What is an deletion mutation?

Deletion of a nucleotide which results in a frameshift. This will likely cause production of a non-functional protein

How can RAG enzymes cause chromosome translocations?

RAG cuts DNA in VDJ regions during recombination

However, RAG can also cut near oncogenes due to recombination signal sequences being present.

This means oncogenes can be incorporated into the D/J regions

Translocation of which gene into the VDJ region is a hallmark of Endemic Burkitt lymphoma?

MYC

Translocation of which gene into the VDJ region is a hallmark of Mantle cell lymphoma?

CCND1

Translocation of which gene into the VDJ region is a hallmark of Follicular lymphoma?

BCL2

What does AID do during somatic hypermutation?

Causes cytidine deamination which results in C (Cytidine) being replaced by U (Uracil)

What is Transition?

Purine nucleotide to a purine nucleotide (E.g. A to G or vice versa)

What is Transversion?

Purine nucleotide to pyrimidine nucleotide/ pyrimidine nucleotide to purine nucleotide (E.g. A to C or G to T)

How can deamination of C to U by AID result in mutations?

If an enzyme called Uracil-N-glycosylase is present it will cleave the U nucleotide away leaving an unpaired base.

Due to many mechanisms this can lead to incorrect repair of DNA and introduction of different nucleotides resulting in mutations.

How can AID induce aberrant SHM in lymphoma?

AID can bind to other transcriptionally active genes and induce somatic hypermutation of these genes resulting in mutations

If this occurs in a regulatory region, this can alter gene expression.

How can AID induce gene translocations?

AID can induce CSR-associated translocations resulting in oncogenes potentially being inserted into IGH switch regions

How can AID induce upregulation of p53?

AID causes DNA breaks

p53 is upregulated when DNA breaks are detected by the cell and p53 upregulates p21 to induce growth arrest and apoptosis

How to germinal centre B-cells prevent p53 from causing apoptosis during AID-induced somatic hypermutation?

Germinal centre B-cells produce BCL6 which downregulates p53, preventing growth arrest and apoptosis

How does binding of BCR/CD40L trigger differentiation of a germinal centre B-cell into a plasma cell?

Binding upregulates NF-kB which upregulates IRF4

IRF4:

• Downregulates BCL6

• Upregulates Blimp1 which also downregulates BCL6

Blimp1 upregulates XBP1 and the cell becomes a plasma cell

How can dysregulated BCL6 (i.e. over expression) promote malignancy of a germinal centre B-cell?

Blocks differentiation into a plasma cell (Downregulates Blimp1)

Promotes mutagenicity (Downregulates p53)

Promotes cell cycle (Downregulates p21)

Many B-cell neoplasms lose surface BCR expression due to Ig-associated translocations and destructive Somatic Hypermutation.

True or False.

False.

Many B-cell neoplasms somehow retain surface BCR expression despite Ig-associated translocations and potentially destructive SHM

What is an indolent lymphoma?

A slow growing or ‘lazy’ lymphoma.

Often causes few initial symptoms and generally doesn’t need immediate treatment