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MIC and MIC-M Classifications of Leukemia
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Metrics ij maxfik ; jk g
ultrametric condition
If the distances between pairs of objects in a phenogram or a hierarchical classification are taken as the dissimilarity level at which the groups they belong to first join, then these distances will satisfy the ultrametric condition. In a phylogenetic tree with tips all at the same level, if distances between pairs of objects are defined as the dissimilarity level of their most recent common ancestors then these distances will also satisfy the ultrametric condition. See also: Metrics; Trees
Metrics F J Rohlf Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1482
A measure, dij, of the dissimilarity between objects i and j is called a distance coefficient if it satisfies the following four conditions for all objects i, j, and k: ij 0 ii 0 ij ji
positivity condition identity condition symmetry condition
ij ik jk
triangle inequality condition
In such cases one can visualize a space, called a pseudometric space, in which objects, such as i and j, correspond to points and dij corresponds to the distance between them. If, in addition, the following condition is satisfied then the distance coefficient defines a metric space: if i 6 j; then ij > 0 definiteness condition This requires that different objects must not be identical. While this condition can easily be violated in small data sets, one assumes that no two objects will be identical if a sufficiently long sequence or enough descriptive variables are obtained. See also: Metric, Four Point; Metric, Manhattan; Metric, Ultra
MIC and MIC-M Classifications of Leukemia B Bain Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1711
From 1986 to 1990, several related international collaborative groups formulated a number of classifications of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), the myelodysplastic syndromes, and the chronic lymphoproliferative disorders. These classifications are based on morphology, immunophenotype, and cytogenetics (MIC). The morphological classification adopted was that of the French±American±British (FAB) group. The MIC classifications resulted from the recognition that immunophenotyping was essential for the diagnosis of some subtypes of leukemia and also that recurring clonal cytogenetic abnormalities permitted the identification of specific disease entities with a greater degree of precision than was possible on the basis of cytology, cytochemistry, and immunophenotype. The application of cytogenetic analysis confirmed that the FAB group's M3 AML and L3 ALL were indeed specific biological entities and, furthermore, confirmed that the FAB group were correct in assigning hypergranular and hypogranular/microgranular promyelocytic leukemia to the same category, since they showed the same recurring cytogenetic abnormality. Cytogenetic analysis also permitted the recognition of entities that did not constitute FAB categories, such as AML associated with t(8;21)(q22;q22) (usually M2 AML), AML associated with inv(16)(p13q22) or t(16;16)(p13;q22) (often M4Eo AML) and AML associated with t(1;22)(p13;q13) (usually M7 AML in infants and young children). The application of the MIC principles of classification led to both scientific and practical advances. For example, the recognition of AML associated with t(8;21) and inv(16) was important not only because it led to new knowledge as to mechanisms of leukemogenesis but also because recognition of the relatively good prognosis of these MIC categories meant that unnecessarily intensive treatment was not given to these patients. There are, however, some MIC categories that are likely to be heterogeneous, rather than representing genuine biological entities. These include AML associated with deletion of the short arm of chromosome 12, and B-lineage or T-lineage ALL associated with deletion of the long arm of chromosome 6. The need to incorporate molecular genetic information into the classification of hematological
M i c ro b i a l Ge n e ti c s 1191 neoplasms led to the proposal, in 1998, of an MIC-M classification of AML and ALL. The MIC-M classification is a refinement of the MIC classification, being based on morphology, immunophenotype, cytogenetic analysis, and molecular genetic analysis (MIC-M). This classification recognizes that it is the nature of the underlying molecular events that determines the characteristics of any neoplasm and that identifying the genetic changes that have occurred will therefore permit more precise and scientifically accurate diagnosis. Furthermore, at a practical level, there are some leukemia-associated chromosomal rearrangements that can be defined only by molecular genetic analysis, either because the banding pattern of the chromosomes concerned is not sufficiently distinctive to permit recognition of an abnormality or because the rearrangement has occurred at a submicroscopic level. The former is the case with t(12;21)(p12;q22) associated with B-lineage ALL, whereas the latter is the case with a deletion upstream of the TAL gene, associated with T-lineage ALL. In addition, cytogenetic analysis may fail so that the application of molecular genetic analysis will permit the accurate diagnosis of more cases of acute leukemia than if reliance is placed only on morphology, immunophenotype, and cytogenetics. An example of the value of the MIC-M approach can be seen in relation to acute hypergranular promyelocytic leukemia (M3 AML) and related disorders. M3 and M3 variant AML represent a single MIC and MIC-M category, since they show the same cytogenetic and molecular genetic abnormality, leukemogenic mechanism, and responsiveness to treatment. However, M3-like AML associated with t(11;17)(q23;q21) shows subtle differences from M3/M3 variant AML. In the latter there is a PMLRARa fusion gene, whereas in the former there is a PLZF-RARa fusion gene; this distinction is of practical as well as scientific significance, since M3/M3 variant AML responds to differentiating therapy with alltrans-retinoic acid, whereas M3-like AML does not. See also: FAB Classification of Leukemia; Leukemia; Leukemia, Acute; Leukemia, Chronic; MLL; WHO Classification of Leukemia
Microarray Technology J Read and S Brenner Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.2095
Microarray technology is a powerful technique used to compare differences in gene expression between
two mRNA samples. Comparing RNA prepared from diseased cells and normal cells can lead to the identification of sets of genes that play key roles in diseases. Genes that are overexpressed or underexpressed in the diseased cells often present excellent targets for therapeutic drugs. The process uses microarray chips, prepared commercially, which comprise numerous wells, each of which contains an isolated gene. mRNA is extracted from the `normal' sample, and a fluorescent labeled cDNA probe is generated, representing all of the genes expressed in the reference sample. A second cDNA probe is generated using a different-colored fluorescent label and mRNA extracted from the `affected' cells. These may be cells exposed to a drug or toxic substance, taken from a tumor or diseased patient, or cells removed at a different time to the `normal' sample. The two fluorescent probe samples are simultaneously applied to a single microarray chip, where they competitively react with the arrayed cDNA molecules. Each well of the microarray is scanned for the fluorescence intensity of each probe, the intensity of which is proportional to the expression level of that gene in the sample. The ratio of the two fluorescent intensities provides a highly accurate and quantitative measurement of the relative gene expression level in the two cell samples. See also: cDNA; Cell Markers: Green Fluorescent Protein (GFP)
Microbial Genetics G M Weinstock Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0824
The genetics of bacteria and bacteriophages played a key role in the development of molecular biology and our knowledge of the flow of genetic information in biological systems. Microbial genetics also provides tools for dissecting many other biological processes. Throughout the twentieth century, particularly the 1940s, these simple organisms provided powerful experimental systems for the study of mutation, inheritance, the structure of the gene, control of gene expression, and the genetic basis of fundamental cellular processes such as intermediary metabolism and DNA recombination and repair. In addition, because many of the microbial experimental systems are pathogens, microbial genetics has provided a powerful approach to the understanding of infectious diseases. The best understood microbial systems, Escherichia coli, Salmonella typhimurium, Bacillus subtilis, and
Metrics ij maxfik ; jk g
ultrametric condition
If the distances between pairs of objects in a phenogram or a hierarchical classification are taken as the dissimilarity level at which the groups they belong to first join, then these distances will satisfy the ultrametric condition. In a phylogenetic tree with tips all at the same level, if distances between pairs of objects are defined as the dissimilarity level of their most recent common ancestors then these distances will also satisfy the ultrametric condition. See also: Metrics; Trees
Metrics F J Rohlf Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1482
A measure, dij, of the dissimilarity between objects i and j is called a distance coefficient if it satisfies the following four conditions for all objects i, j, and k: ij 0 ii 0 ij ji
positivity condition identity condition symmetry condition
ij ik jk
triangle inequality condition
In such cases one can visualize a space, called a pseudometric space, in which objects, such as i and j, correspond to points and dij corresponds to the distance between them. If, in addition, the following condition is satisfied then the distance coefficient defines a metric space: if i 6 j; then ij > 0 definiteness condition This requires that different objects must not be identical. While this condition can easily be violated in small data sets, one assumes that no two objects will be identical if a sufficiently long sequence or enough descriptive variables are obtained. See also: Metric, Four Point; Metric, Manhattan; Metric, Ultra
MIC and MIC-M Classifications of Leukemia B Bain Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1711
From 1986 to 1990, several related international collaborative groups formulated a number of classifications of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), the myelodysplastic syndromes, and the chronic lymphoproliferative disorders. These classifications are based on morphology, immunophenotype, and cytogenetics (MIC). The morphological classification adopted was that of the French±American±British (FAB) group. The MIC classifications resulted from the recognition that immunophenotyping was essential for the diagnosis of some subtypes of leukemia and also that recurring clonal cytogenetic abnormalities permitted the identification of specific disease entities with a greater degree of precision than was possible on the basis of cytology, cytochemistry, and immunophenotype. The application of cytogenetic analysis confirmed that the FAB group's M3 AML and L3 ALL were indeed specific biological entities and, furthermore, confirmed that the FAB group were correct in assigning hypergranular and hypogranular/microgranular promyelocytic leukemia to the same category, since they showed the same recurring cytogenetic abnormality. Cytogenetic analysis also permitted the recognition of entities that did not constitute FAB categories, such as AML associated with t(8;21)(q22;q22) (usually M2 AML), AML associated with inv(16)(p13q22) or t(16;16)(p13;q22) (often M4Eo AML) and AML associated with t(1;22)(p13;q13) (usually M7 AML in infants and young children). The application of the MIC principles of classification led to both scientific and practical advances. For example, the recognition of AML associated with t(8;21) and inv(16) was important not only because it led to new knowledge as to mechanisms of leukemogenesis but also because recognition of the relatively good prognosis of these MIC categories meant that unnecessarily intensive treatment was not given to these patients. There are, however, some MIC categories that are likely to be heterogeneous, rather than representing genuine biological entities. These include AML associated with deletion of the short arm of chromosome 12, and B-lineage or T-lineage ALL associated with deletion of the long arm of chromosome 6. The need to incorporate molecular genetic information into the classification of hematological
M i c ro b i a l Ge n e ti c s 1191 neoplasms led to the proposal, in 1998, of an MIC-M classification of AML and ALL. The MIC-M classification is a refinement of the MIC classification, being based on morphology, immunophenotype, cytogenetic analysis, and molecular genetic analysis (MIC-M). This classification recognizes that it is the nature of the underlying molecular events that determines the characteristics of any neoplasm and that identifying the genetic changes that have occurred will therefore permit more precise and scientifically accurate diagnosis. Furthermore, at a practical level, there are some leukemia-associated chromosomal rearrangements that can be defined only by molecular genetic analysis, either because the banding pattern of the chromosomes concerned is not sufficiently distinctive to permit recognition of an abnormality or because the rearrangement has occurred at a submicroscopic level. The former is the case with t(12;21)(p12;q22) associated with B-lineage ALL, whereas the latter is the case with a deletion upstream of the TAL gene, associated with T-lineage ALL. In addition, cytogenetic analysis may fail so that the application of molecular genetic analysis will permit the accurate diagnosis of more cases of acute leukemia than if reliance is placed only on morphology, immunophenotype, and cytogenetics. An example of the value of the MIC-M approach can be seen in relation to acute hypergranular promyelocytic leukemia (M3 AML) and related disorders. M3 and M3 variant AML represent a single MIC and MIC-M category, since they show the same cytogenetic and molecular genetic abnormality, leukemogenic mechanism, and responsiveness to treatment. However, M3-like AML associated with t(11;17)(q23;q21) shows subtle differences from M3/M3 variant AML. In the latter there is a PMLRARa fusion gene, whereas in the former there is a PLZF-RARa fusion gene; this distinction is of practical as well as scientific significance, since M3/M3 variant AML responds to differentiating therapy with alltrans-retinoic acid, whereas M3-like AML does not. See also: FAB Classification of Leukemia; Leukemia; Leukemia, Acute; Leukemia, Chronic; MLL; WHO Classification of Leukemia
Microarray Technology J Read and S Brenner Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.2095
Microarray technology is a powerful technique used to compare differences in gene expression between
two mRNA samples. Comparing RNA prepared from diseased cells and normal cells can lead to the identification of sets of genes that play key roles in diseases. Genes that are overexpressed or underexpressed in the diseased cells often present excellent targets for therapeutic drugs. The process uses microarray chips, prepared commercially, which comprise numerous wells, each of which contains an isolated gene. mRNA is extracted from the `normal' sample, and a fluorescent labeled cDNA probe is generated, representing all of the genes expressed in the reference sample. A second cDNA probe is generated using a different-colored fluorescent label and mRNA extracted from the `affected' cells. These may be cells exposed to a drug or toxic substance, taken from a tumor or diseased patient, or cells removed at a different time to the `normal' sample. The two fluorescent probe samples are simultaneously applied to a single microarray chip, where they competitively react with the arrayed cDNA molecules. Each well of the microarray is scanned for the fluorescence intensity of each probe, the intensity of which is proportional to the expression level of that gene in the sample. The ratio of the two fluorescent intensities provides a highly accurate and quantitative measurement of the relative gene expression level in the two cell samples. See also: cDNA; Cell Markers: Green Fluorescent Protein (GFP)
Microbial Genetics G M Weinstock Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0824
The genetics of bacteria and bacteriophages played a key role in the development of molecular biology and our knowledge of the flow of genetic information in biological systems. Microbial genetics also provides tools for dissecting many other biological processes. Throughout the twentieth century, particularly the 1940s, these simple organisms provided powerful experimental systems for the study of mutation, inheritance, the structure of the gene, control of gene expression, and the genetic basis of fundamental cellular processes such as intermediary metabolism and DNA recombination and repair. In addition, because many of the microbial experimental systems are pathogens, microbial genetics has provided a powerful approach to the understanding of infectious diseases. The best understood microbial systems, Escherichia coli, Salmonella typhimurium, Bacillus subtilis, and