Abstract
Beginning with the discovery of the Philadelphia chromosome in 1960, our descriptions and definitions of hematological malignancies have been successively refined and revised to include morphological, immunophenotypic, and molecular genetic features. As hematopathologists, we now see beyond architectural and cytologic alterations and have, to some degree, become molecular morphologists. Indeed, our “view” of diseases now includes a rudimentary understanding of the molecular genetic abnormalities present in the cells we study under the microscope.
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Perhaps the two best known examples of this are all-trans retinoic acid (ATRA) for AML-M3 with the t(15;17) and the tyrosine kinase inhibitor STI-571 in CML. The t(15:17) results in the fusion of the zinc finger-containing gene PML and nuclear hormone receptor RAR gene (Melnick and Licht 1999). Detection of this translocation helps to confirm the morphological diagnosis. The PML-RAR fusion protein has enhanced interaction with the N-CoR/Sin3/HDAC1 co-repressor apparatus and thus functions as a transcriptional repressor (Melnick and Licht 1999). ATRA at pharmacological concentrations overcomes this interaction (Tallman 1998). In CML, the presence of the bcr-abl translocation also helps define the disease entity. At the biological level, the translocation constitutively activates the abl tyrosine kinase (Thijsen et al. 1999). This leads to malignant transformation through interference in normal cellular processes such as cell growth, adhesion, and cell death. One of the most exciting developments in rational drug design is the tyrosine kinase inhibitor STI-571, which targets this abnormally activated tyrosine kinase. Clinical trials of STI-571 show great promise as a new treatment modality (Kantarjian et al. 2000).
Although specific therapies are not as far advanced in the area of mature B-lymphoid malignancies, significant progress is being made in the molecular genetic classification of disease. Two examples include B-cell chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). In CLL, two subtypes have recently been defined based on mutational status of the immunoglobulin heavy chain (IgH) gene. Cases demonstrating somatic mutation, similar to post-germinal center B-cells, have a significantly better survival than those with germline IgH genes (Hamblin et al. 1999). This molecular genetic subdivision of CLL is changing our concept of the disease and appears to help us distinguish between clinically and biologically distinct diseases within a morphologically uniform group. Considerable excitement has also been generated by the analysis of DLBCL with high-density expression arrays. It is well known that DLBCL is a biologically heterogeneous disease. This is reflected in the clinical behavior of patients with DLBCL. Attempts are now being made to classify these cases at the molecular genetic level. In a series of well-characterized DLBCLs, two major types of DLBCL were identified by their patterns of gene expression: the activated B-cell-like and the germinal center-like types (Alizadeh et al. 2000). The patients with the former type of DLBCL had a significantly worse outcome compared to those with the latter type, even when stratified by standard clinical prognostic parameters.
These examples illustrate our movement into a new era of molecular genetic classification, molecular diagnosis, and rational drug design in hematological malignancy. They may be seen as paradigms for the application of molecular genetic tools to help separate and define distinct diseases. The unique patterns of tumor gene expression (transcriptomes) and protein expression (proteomes) may then serve as the basis for developing targeted therapies for these molecularly defined entities.