12-1: 1/9 - Introduction To Hematologic Malignancies

Front 1

What is a leukemia?

Back 1

Clonal malignant neoplasm of hematopoietic cells originating in and accumulating in BM and peripheral blood

Front 2

What is a lymphoma?

Back 2

Clonal proliferation of malignant WBCs arising in lymphoid tissues (LNs or extranodal lymphatic tissue)

Lymphadenopathy is key feature.

Front 3

What is the most common form of cancer in children?

Back 3

Leukemia (40%)

Front 4

Infectious cause of lymphadenopathy.

Back 4

Mononucleosis
(and acute HIV)

Front 5

Normal size of LNs.

Back 5

≤1cm

Front 6

What is the hallmark of hematopoietic malignancy?

Back 6

Clonal hematopoiesis resulting in a homogenous distribution of genetically related malignant cells.

Front 7

How and when can G6PD isoenzyme analysis determine the presence of clonality?

Back 7

G6PD is x-linked.

Useful in women that are heterozygous for G6PD because random inactivation of X chromosome allows for mosaic of cells that express G6PD isoenzyme A and G6PD isoenzyme B.

A monoclonal malignant tumor would only demonstrate a single isoenzyme.

Front 8

How can Ig light chain expression detect malignant clonality?

Back 8

Normal B lymphocytes should express an Ig light chain, should make both kappa and lambda light chains.

If do an immunoperoxidase stain for kappa light chains and a stain for lambda light chains, should see one (not both) in a clonal malignancy.

Front 9

Life of a B Cell.

Begin with location of hematopoietic stem cell.

How does this differ with T cells?

Back 9

Hematopoietic stemm cell in marror
Lymphoid progenitor migrates to BM, thymus
then Early B precursor (heavy chain rearrangement)
-->Pre-B
-->Naive B Cell (antigen-naive; undergoes heavy and light chain rearrangement)
-->migrates to LNs

Note:
B cell gene rearrangement occurs in marrow
T cell gene rearrangement occurs in thymus

Front 10

VDJ recombination allows for ________.

Back 10

Antigen receptor diversity of HSC and lymphoid progenitors in BM

Front 11

Role of TdT (terminal deoxyribonucleotidyl transferase).

Back 11

Adds random nucleotides to VDJ recombination sites in order to achieve add'l Ag diversity.

Front 12

How can Southern Blot (DNA) analysis detect clonality?

What would you expect to see on electrophoresis?

Back 12

Normal heterogenous population of lymphocytes with include cells w/varied Ig (or TCR in case of T cells) rearrangements.

Southern blotting of a lymphoid malignancy would demonstrate a single band representing a population of cells containing identical gene rearrangement, an indication of clonality.

HOWEVER, there would be an additional band, shared with the control electrophoresis as this band represents unrearranged "germline" bands.

In short, lymphomas have an extra band on Southern Blot.

Front 13

How is PCR used to detect Ig rearrangements?

What would you expect to see?

Back 13

No band in normal.

One band in lymphoma.

Front 14

What specific molecular defects allow for detection of clonality?

Back 14

Oncogenes
Tumor suppressor genes (p53)
Genes regulating apoptosis
Genes involve din DNA repair

Front 15

After recombination, B lymphocytes express ____.

Then where do they go? What occurs here?

Discuss primary and secondary follicles.

Back 15

After recombination, B cells express IgM and IgD, and migrate to peripheral lymphoid tissues. The cell is mature, but antigen-naive.

Some B cells become plasma cells in medullary cords and secrete IgM.

Most cells to go PRIMARY FOLLICLES. Activtn by specific Ag results in stimulation of B cells proliferation and clonal expansion.

B cell centroblasts (dividing cells) form secondary follicles (GERMINAL CENTERS) and are surrounded by Th2 cells. Many germinal centers arise.

Front 16

What is somatic hypermutation?

Where does it occur?

Back 16

In germinal centers (secondary follicles), B cells undergo clonal expansion and rapidly proliferate.

The Ig genes of the B cells are susceptible to point mutations in the variable region. This mutative portion = somatic hypermutation.

Occurs in germinal center!

Front 17

What is affinity maturation?

Back 17

B cells that have developed mutations during somatic hypermutation are rescued from apoptosis by binding to Ag on dendritic cells. Known as AFFINITY MATURATION.

Front 18

What is class switch recombination? When does it occur?

What cells are necessary?

Back 18

After affinity maturation, B cells switch from IgM to IgG, IgA, and IgE.

This process depends on T helper cells.

Front 19

TdT positive cells are located in the _______.

Back 19

BM, Thymus

TdT- in peripheral lymphoid tissue.

Front 20

Life of a T cell.

Back 20

HSC-->Lymphoid Progenitor Cell-->Early Thymocyte-->Common Thymocyte
-->CD8 (cytotoxic T cell)
OR
-->CD4 (helper T cell)
THIS OCCURS IN THYMUS

After this point, travel to LNs and become peripheral T cells

Front 21

Which T cell progenitor is double-negative? What does this mean?

Back 21

Early thymoctes are double negative because don't express CD4 or CD8

Front 22

Which T cell progenitor is double positive? What does this mean?

Back 22

Common Thymocyte bc expresses CD4 AND CD8

Front 23

Lower CD numbers correlate with ____.

Back 23

T cells

Front 24

Higher CD numbers correlate with ____.

Which numbers specifically?

Back 24

B cells (CD numbers in the teens--10 included, twenties)

Front 25

CD34+ is a _______.

Back 25

Hematopoietic SC

Front 26

CD34+ Tdt+ is a _______.

Back 26

Lymphoid progenitor cell.

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