Recent studies in mice engineered to express regulatable alleles of MYC, RAS, and other oncogenes support the general principle that the genetic lesions that initiate tumorigenesis are often essential to maintain the malignant phenotype. The general design of many of these experiments may be criticized on theoretical grounds because, unlike human cancer, the inciting mutation is expressed widely in a field of cells and this may result in polyclonal proliferation that obviates the need for one or more cooperating mutations. But studies in human patients with chronic myeloid leukemia (CML) who demonstrate resistance to imatinib provide strong support for the idea that genetic lesions that initiate tumorigenesis remain essential in at least some human cancers (reviewed in Shannon, Cancer Cell. 2002;2:99-102).
In this issue Karlsson and coworkers (page 2797) describe an interesting series of experiments in which they performed spectral karyotype (SKY) analysis in lymphomas from mice in which the tetracyclene regulatory system was used to conditionally express theMYC oncogene in B cells. They then correlated these data with the propensity of these tumors to bypass the requirement forMYC in vivo. The authors emphasize that tumors from these mice are genetically complex yet consistently regress whenMYC expression is repressed. This is a fair point, but I find other aspects of this work more interesting. First, a significant proportion of tumors in this model relapse despite continuous inhibition of MYC expression and no longer require the inciting oncogene. Second, there was an intrinsic difference in the propensity of individual tumors to relapse; that is, the intrinsic genetic characteristics of the primary lesions correlated with whether the tumor had a high, intermediate, or low probability of becoming independent of the requirement for MYC. Finally, specific new recurring chromosomal translocations were identified in resistant lymphomas.
To physicians who treat patients with hematologic malignancies, this sounds very much like what occurs in the clinic. These data and other recent studies (see, for example, Le Beau et al, Blood. 2002;89:2985-2991) underscore that careful molecular and cytogenetic analysis of tumors that develop in mouse cancer models may offer new ways of identifying cooperating mutations and of uncovering the molecular mechanisms that underlie disease progression and treatment resistance.
- Copyright © 2003 The American Society of Hematology