Blood, 1 April 2003, Vol. 101, No. 7, pp. 2451-2451
Bypassing the requirement for MYC in lymphoma
progression
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 the
MYC oncogene in B cells. They then correlated these data
with the propensity of these tumors to bypass the requirement for
MYC in vivo. The authors emphasize that tumors from these
mice are genetically complex yet consistently regress when
MYC 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.
Kevin Shannon
University of California, San
Francisco
