Chapter 13.3 Neoplastic proliferation of white cells Flashcards
etiology and pathogenesis of white cell neoplasia–chromosomal translocations and other acquired mutations
- nonrandom chromosomal abnormalities, most commonly translocations are present in the majority of white cell neoplasms!!
- Many specific rearrangements are associated with particular neoplasms suggesting critical role in genesis
The genes that are mutated or otherwise altered in white cell neoplasia often play crucial roles in?
- development, growth or survival of normal counterpart of the malignant cell
- consequently, certain mutations are associated with specific tumor types
- sometimes, mutation produces a “dominant negative” protein that interferes with normal function (loss of function); in others the result is an inappropriate increase in some normal activity (gain of fnx)
White cell neoplasia etiology–oncoproteins created by genomic aberrations often
-block normal maturation, turn on pro-growth signaling pathways or protect cells from apoptotic cell death
Oncogenic events that serve as oncogenic driver mutations in particular kinds of white cell malignancies
- many oncoproteins cause arrest in differentiation when cells are proliferating rapidly–important in acute leukemias in which dominant negative oncogenic mutations involving transcription factors are present that interfere with early stages of lymphoid of myeloid cell differentiation
- mutations in transcriptional regulators–enhance self renewal of tumor cells giving them stem-cell like properties; these mutations collaborate with mutations that produce a constituitively active tyrosine knase; downstream signaling arms, the PI3K/AKT and MAPK pathways and derive cell growth and Warburg metabolism
- Mutations that inhibit apoptosis–certain hematologic malignancies
How are proto-oncogenes activated in lymphoid cells?
-by errors that occur during Ag receptor gene rearrangement and diversification!
Among lymphoid cells, potentially ocogenic mutations occur most frequently in
-germinal center B cells during attempted Ab diversification; after Ag stimulation, B cells enter germinal centers and upregulate the expression of activation-induced cytosine deaminase (AID), a specialized DNA-modifying enzyme that is essential for class switching and somatic hypermutation
class switching
-intragenic remcombination event where the IgM heavy chain constant gene segment is replaced with a different constant segment (IgG3) leading to a switch in the class (isotype) of Ab produced
somatic hypermutation
-creates point mutations within Ig genes that may increase Ab affinity for Ag
MYC protooncogene
- activated in germinal center B-cell lymphomas by translocations to transcriptionally active Ig locus
- AID expression is sufficient to induce MYC/Ig translocations in normal germinal center B cells, apparently because AID creates lesions in DNA that lead to chromosomal breaks
BCL6 protooncogene
-transcription factor that has important role in many B-cell malignancies; frequently activated in germinal center-B cell lymphomas by point mutations that also stem from mistargeted DNA breaks induced by AID
regulated genomic instability unique to precursor B and T cells:
- express a V(D)J recombinase that cuts DNA at specific sites within the Ig and T cell receptor loci, respectively
- process is essential for the assembly of productive Ag receptor genes but sometimes goes awry leading to joining of portions of other genes to Ag receptor gene regulatory elements
- esp in tumors of precursor T cells, proto-oncogenes are often deregulated by their involvement in aberrant recombination events
Pathogenesis of white cell malignancies
- tumors harbor mutations that principally effect maturation or enhance self-renewal, drive growth or prevent apoptosis
- Progrowth mutations: tyrosine kinase mutations, MYC translocation–increased cell division, Warburg metabolism
- Mutations in TFs that influence self renewal (MLL translocation, PML-RARA fusion gene)
- Pro-survival mutations: BCL2 translocation
Inherited genetic factors in white cell neoplasias
- ppl with genetic diseases that promote genomic instability such as Bloom syndrome, Fanconi anemia, and ataxia telangiectasia are at increased risk of acute leukemia
- Also both Down syndrome and NF type 1 are associated with increased risk of childhood leukemia
Viruses and white cell malignancies
-3 viruses: HTLV-1, EBV, and Kaposi sarcoma herpesvirus/ HHV8=causative agents in particular lymphomas
HTLV-1 is associated with which malignancies?
-adult T-cell leukemia/lymphoma
EBV associated with?
Burkitt lymphoma, 30-40% of Hodgkin lymphoma, many B-cell lymphomas arising in the setting of T-cell immunodeficiencies and rare NK-cell lymphomas
KSHV is associated with
-Kaposi sarcoma and unusual B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity
Chronic inflammation and white cell malignancies
- localized chronic inflammation predispose to lymphoid neoplasia–almost always arises within inflammed tissue
- H. pylori–>gastric B cell lymphomas
- gluten sensitive enteropathy–>intestinal T-cell lymphomas
- breast implants–>unusual T cell lymphoma subtype
- HIV infxn–> B cell lymphomas that may arise within any organ
HIV infection and B cell lymphoma pathogenesis
- early on, T-cell dysregulation of HIV causes a systemic hyperplasia of germinal center B cells that is associated with an increased incidence of germinal center B-cell lymphomas
- In advanced infection (AIDS), severe T-cell deficiency further elevates risk for B-cell lymphomas, esp those associated with EBV and KSHV/HHV-8
Iatrogenic factors and white cell malignancies
-radiation therapy and certain chemotherapies increase risk of myeloid and lymphoid neoplasms due to mutagenic effects of ionizing radiation and chemotherapeutic drugs on hematolymphoid progenitor cells
Smoking and white cell malignancies
-smokers have 1.3-2x increased incidence of acute myeloid leukemia bc of exposure to carcinogens like benzene in tobacco smoke
Lymphoid neiplasms–Leukemia vs. lymphoma definitions
- Leukemia: neoplasms that present with widespread involvement of bone marrow and usually (but not always) the peripheral blood
- Lymphoma: proliferations that arise in discrete tissue masses
- blurred division bw the two
