Myeloid Malignancies

Abstract

A wealth of information is available regarding genetic abnormalities that contribute to human myeloid malignancies. Modeling these mutations in mice has been facilitated by the ability to manipulate the hematopoietic system not only through germline modification but also by retroviral transduction of bone marrow. Chimeric fusion proteins resulting from balanced chromosomal aberrations as well as intragenic mutations have been introduced into mice to generate models of many types of human myeloid leukemias. These models recapitulate important features of the human diseases and have been utilized to elucidate mechanisms through which particular genetic changes contribute to myeloid neoplasia. The study of human myeloid neoplasms has led to many advances in our understanding of these disorders and of other human malignancies. The association of specific chromosomal changes in neoplastic cells with particular malignancies was begun by the identification of the Philadelphia chromosome in chronic myelogenous leukemia (CML) (Nowell, ). CML has remained a leading source of insight into the pathogenesis and treatment of human neoplasms: from identifying that the Philadelphia chromosome creates an oncogenic BCR/ABL fusion protein to the development of imatinib mesylate as a molecularly targeted therapeutic agent. In addition to the t(9;22) of CML, numerous recurrent balanced chromosomal aberrations have been identified in human myeloid neoplasms. In fact, the genes altered by all of the major (and many of the minor) balanced aberrations of myeloid leukemia have been identified. Most of these aberrations result in the production of abnormal fusion proteins, while others result in dysregulated gene expression. In addition, a substantial number of recurrent point mutations and small intragenic changes have also been associated with human leukemias and related disorders. Because there is a wealth of information regarding the genetic changes that are present in these human diseases, it has been possible to model numerous such changes in mice.