Childhood leukemia is a disease of many different subtypes. We study one of them named “acute promyelocytic leukemia” (APL) that has unique features: (i) the disease is more common in Latino countries than other parts of the world, and (ii) the disease occurs sometimes as secondary cancer (after prior chemotherapy), suggesting a chemical cause.
APL is a medical emergency requiring prompt diagnosis and management.At the molecular level, APL presents a chromosomal aberration [t(15;17)(q24;q21)], which creates the chimeric PML-RARα fusion. The gene RARais the retinoic acid receptor alpha, which binds retinoic acid at the nuclear level. Retinoids are natural or synthetic derivatives of vitamin A and they are necessary dietary constituents that exert effects on development, proliferation, and differentiation in normal cells. The fusion PML–RARabehaves as an altered retinoic acid receptor altering the cell signaling and inducing this subtype of leukemia. Interestingly, supra physiologic concentrations of retinoic acid (in the form of all-trans retinoic acid, or ATRA), target the oncogenic protein PML-RARaand determines the basis of the APL therapy. Thus, the story of APL can serve as a model for the development of targeted therapies and curative approaches for malignant diseases.
In the United States, as in Central and Northern Europe, the percentage of APL is
5-7% of all pediatric acute myeloid leukemia (AML) cases; a higher frequency (20-30%) is reported in children of Latino/Hispanic ancestry. Ethnic variability and environmental factors may account for the different incidence of APL in the various countries.
Insights into the mechanisms of PML-RARaformation can be gained from therapy related APL (t-APL). In this model, chromosomal translocations are consequence of cytotoxic agents given for the primary disease. These agents target the enzyme topoisomerase II alpha (TOP2A), a DNA-binding dimeric protein which produces double-strand breaks in the DNA. With altered activity, TOP2A generate translocations that induce acute leukemia, generally arising within 3 years. Breakpoints in t-APL cases following mitoxantrone exposure for prior breast carcinoma were found to be clustered in a region within PMLintron 6 (red arrows, Figure 1; Modified from Mays et al, 2010, Blood). Analysis of these regions should contribute to our understanding of the precise molecular mechanisms that are responsible for the generation of translocations in leukemia.
Understanding the genetic predisposition to APL is fundamental to any hope in prevention. It is indeed also necessary to understand the role of the environment, since environmental exposures may interact with constitutive factors to cause the disease.