Porth's Essentials of Pathophysiology, 4e

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Hematopoietic Function

U N I T 3

Because blood cells circulate throughout the body, these neoplasms are often disseminated from the onset. The leukemic cells may also infiltrate the liver, spleen, lymph nodes, and other tissues throughout the body, causing enlargement of these organs. Classification The leukemias commonly are classified according to their predominant cell type (i.e., lymphocytic or myelocytic) and whether the condition is acute or chronic. Biphenotypic leukemias demonstrate char- acteristics of both lymphoid and myeloid lineages. The lymphocytic leukemias involve immature lym- phocytes and their progenitors that originate in the bone marrow but infiltrate the spleen, lymph nodes, CNS, and other tissues. The myelogenous leukemias, which involve the pluripotent myeloid stem cells in bone marrow, interfere with the maturation of all blood cells, including the granulocytes, erythrocytes, and thrombocytes. A rudimentary classification system divides leuke- mia into four types: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelocytic leukemia (AML), and chronic myelocytic leukemia (CML). 4,7 Among children and adolescents, ALL is the most common type, accounting for 75% of leukemia cases. In adults 20 years of age and older, the most com- mon types are CLL (38%) and AML (30%). 16 Etiology and Molecular Biology The causes of leukemia are largely unknown and likely differ among the different types of leukemia. The inci- dence of acute leukemia among persons who have been exposed to high levels of radiation is unusually high. Exposure to ionizing radiation, including medical radiation used in cancer treatment, increases the risk of leukemia. 16 Leukemia may occur as a second can- cer after aggressive chemotherapy for other cancers, such as Hodgkin lymphoma. Some factors are associ- ated with increased risk of certain types of leukemias. 16 Exposure to certain chemicals such as formaldehyde and benzene (a compound in cigarette smoke and gaso- line) also increases the risk of AML. Family history is one of strongest risk factors for CLL. The existence of a genetic predisposition to development of acute leukemia is suggested by the increased leukemia incidence among a number of congenital disorders, including trisomy 21 (Down syndrome), neurofibromatosis, and Fanconi ane- mia. 7,16 In individuals with Down syndrome, the inci- dence of acute leukemia is 10 to 20 times that of the general population. The molecular biology of leukemia suggests that the event or events causing the disorders exert their effects through disruption or dysregulation of genes that normally regulate blood cell development, blood cell homeostasis, or both. Most commonly, these are structural changes classified as translocations , in which a part of one chromosome becomes located on another chromosome and vice versa; inversions , in which part of

a chromosome turns upside down and now is in reverse order but still attached to the original chromosome; and deletions , in which part of a chromosome has been lost (see Chapter 6). It is the disruption or dysregulation of specific genes and gene products occurring at the site of these chromosome aberrations that contributes to the development of leukemia. 17 In many instances, these genes and their products have been shown to be directly or indirectly involved in the normal development or maintenance of the hematopoietic system. Thus, it would appear that leukemia results, at least in part, from disruption in the activity of genes that normally regulate blood cell development. Advances in the under- standing of the molecular biology of leukemia are begin- ning to provide a more complete understanding of the molecular complexity of this disorder for the purposes of diagnosis, classification, treatment, and monitoring of clinical outcomes. One of the more studied translocations is the Philadelphia chromosome, which was the first chromo- somal abnormality identified in cancer. The Philadelphia chromosome translocation represents a reciprocal trans- location between the long arm of chromosome 22 and the long arm of chromosome 9. 17,18 During the trans- location, a large portion of 22q is translocated to 9q, and a smaller piece of 9q is moved to 22q (Fig. 11-6). The portion of 9q that is translocated contains ABL,

Normal chromosomes

Chromosome 22

Chromosome 9

BCR locus

ABL proto- oncogene

Myelogenous leukemia

BCR locus

BCR–ABL hybrid gene

ABL oncogene

ABL protein

FIGURE 11-6. The Philadelphia (Ph) chromosome is formed by breaks at the ends of the long arms of chromosomes 9 and 22, allowing the ABL proto-oncogene on chromosome 9 to be translocated to the breakpoint cluster region (BCR) on chromosome 22.The result is a new fusion gene coding for the BCR–ABL protein, which is presumably involved in the pathogenesis of chronic myelogenous leukemia.