NEOPLASIA III- MOLECULAR ASPECTS OF NEOPLASIA IN HEMATOLOGY

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I. INTRODUCTION
II. MOLECULAR MECHANISMS IN HEMATOLOGIC NEOPLASIA
III. SUMMARY

I. INTRODUCTION

• Components of the Hematopoietic System
  
  
• Neoplastic Hematopathology
  
  
  • Leukemia- bone marrow based malignancy
    • Acute vs. chronic leukemia
    • Lymphocytic vs. myelogenous leukemia
  • Lymphoma- lymph node based malignancy
    • NonHodgkin's lymphoma- neoplasm of lymphocytes
    • Hodgkin's disease

II. MOLECULAR MECHANISMS IN HEMATOLOGIC NEOPLASIA

• General
  
  
  • Oncogene activation by chromosomal translocation oncogenes become activated by insertion into a new transcriptional environment in which they become "turned on"
    e.g., Burkitt's lymphoma - t(8;14); c-myc oncogene (8), (an oncogene which stimulates proliferation but stops differentiation,) is translocated to immunoglobulin heavy chain gene, (14) and becomes overexpressed from immune stimulation follicular center cell lymphoma- t(14;18); the bcl-2 oncogene, a gene which interrupts programmed cell death, is translocated to the immunoglobulin heavy chain gene (14)
    
    
  • Oncogene activation by point mutation
    • ras mutations found in 10-30% of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocyte leukemia, and multiple myeloma
      
      
  • Oncogene activation by gene amplification
    • not important in hematologic neoplasms

    
    

  • Loss of tumor suppressor genes
    • Rb1 and p53 mutations seen in lymphoma and leukemia (especially Burkitt lymphoma and chronic lymphocyte leukemia)
      
      
  • Multistep nature of hematologic malignancies
    • No single oncogene or tumor suppressor gene alteration will produce a malignancy. Apparently, a number of these changes are needed to act in concert to produce the neoplasm
      • e.g., AML - ras, p53 mutations, other specific translocations (i.e., t(8;21), t(15;17), etc).
      • Burkitt's lymphoma - c-myc activation, p53 and Rb1 mutations
        
        
• Chronic Myelogenous Leukemia (CML)
  
  
  • Clinical and Pathologic features
    • Clinical
      • mean age: late middle age
      • insidious onset: fatigue, splenomegaly
      • mean survival: 5 years
    • Pathogenesis
      • Irradiation and toxic chemical exposure (benzene) have been implicated in causation of CML; these are agents which damage DNA. In many cases, however, no causative agent can be identified.
    • Morphologic features
      • Peripheral blood: elevated leukocyte count due to leukemic cells (neutrophils, myelocytes, basophils)
      • Bone marrow: hypercellular due to overgrowth of clonal cells
  • Molecular Aspects of CML
    • Cytogenetics of CML
      • Philadelphia chromosome- t(9;22); translocation that occurs in almost every case of CML in which a portion of chromosome 9 and chromosome 22 are physically exchanged.
    • Molecular genetics
      • Genes located at chromosome breakpoints
        • 9: c-abl oncogene codes for a protein product (tyrosine kinase) of 145 kd
        • 22: breakpoint cluster region (bcr) codes for a protein product of 160 kd, whose function is unknown
      • Fusion gene produced by translocation
        • bcr/abl- codes for protein product of 210 kds; has avid tyrosine kinase activity (much greater than normal c-abl gene product); this increased activity is critical in pathogenesis of the leukemia.

III. SUMMARY

DNA drives cellular processes, including those which determine cell proliferation and death. Changes in the cellular DNA complement- both qualitative and quantitative- will directly affect these processes, in particular when they involve oncogenes. The majority of hematologic malignancies have reproducible chromosomal abnormalities manifest at either the "gross" (cytogenetic) or molecular level and these often occur at oncogenic loci; it is clear that those changes are important in the propagation of the neoplastic process.


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Neoplasia I: Introduction to Neoplasia
Neoplasia II: Molecular Pathobiology of Neoplasia

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