Defining a Unique Role of a Tumor Suppressing Gene in Childhood Leukemia
Acute B lymphoblastic leukemia (B-ALL) is the most common childhood cancer. It is a malignancy that affects a population of white blood cells, termed B-cells that are an essential component of the immune system and host defense. It turns out that B-ALL is actually a collection of different subtypes, some of which are more aggressive than others due to the nature of the genetic defect(s). One subtype in particular is Philadelphia chromosome-positive (Ph+) B-ALL, which results from a type of genetic alteration historically aligned with a poor prognosis.
Because of the great clinical challenges that these children face, there is a compelling need to develop new therapeutic paradigms. Interestingly, a similar genetic lesion is found in adult patients with Ph+ B-ALL, as well as adult patients with a blood cancer known as chronic myeloid leukemia (CML). Thus, knowledge gained from the proposed research may be applicable not only to pediatric Ph+ B-ALL, but also to a range of cancer types that share a common basis of tumor development, maintenance or progression.
Ironically, the molecular events that drive the development of a cancer can be an ‘Achilles heel’ and represent novel targets of drugs that interfere with those tumor-promoting activities. In the case of pediatric Ph+ B-ALL, it is hypothesized that interferon regulatory factor-4 (IRF4) constitutes an integral component of disease pathogenesis and, therefore, a rationale target for therapeutic intervention. Ordinarily, the production of the IRF4 protein is indispensable for normal B cell development. This seminal finding was elegantly unveiled in models engineered to lack IRF4 expression, which greatly accelerated the formation of a B-ALL-like disease akin to that found in humans. In fact, adult patients with Ph+ B-ALL display a profound loss of IRF4 expression.
Altogether these findings support a new model in which the development, maintenance or progression of pediatric Ph+ B-ALL is IRF4-dependent; that is, the lower the level of IRF4, the higher is the likelihood of exacerbating disease severity and vice versa. The ability of IRF4 to function in such a capacity raises the notion that IRF4 can behave as a tumor suppressor gene, one endowed with the ability to alter the course of disease by controlling the expression of subsequent genes vital for cancer cell survival and growth.
Through the generous support from the Roswell Park Alliance Foundation, Dr. Scott Abrams is leading research that will make use of appropriate model systems to build on this rationale and advance our understanding of: 1) mechanisms that regulate IRF4 expression; and 2) the importance of IRF4 expression in response to novel experimental therapeutics.Thus, these studies have the potential to define for the first time IRF4 as a tumor suppressor gene in pediatric Ph+ B-ALL, which it is hoped will lead to the discovery of new ways to treat children with such a devastating cancer.