AID-Mediated Genetic Instability in Bcr-Abl1-Transformed B Cell Lineage Leukemia

Sponsor: NIH National Cancer Institute

Location(s): United States


The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 kinase, which drives two types of leukemia: Acute lymphoblastic leukemia (Ph+ ALL) is derived from a transformed B lymphocyte and chronic myeloid leukemia (CML) originates from myeloid cells that would otherwise develop into macrophages or monocytes. While Ph+ ALL represents a rapidly progressive disease already at the outset, the course of CML is typically stable over many years and only shows rapid progression in the terminal stage, the so-called "blast crisis". The reasons leading to progression from chronic phase into blast crisis are largely unknown. The treatment of both Ph+ ALL and CML has been revolutionized by the discovery of the BCR-ABL1 kinase-inhibitor Imatinib. However, even though both leukemia types carry the same genetic abnormality, the outcome of Imatinib-treatment is strikingly different: whereas Imatinib is very effective in the treatment of chronic phase CML, treatment success is only transient for patients with Ph+ ALL or blast crisis CML. In these patients, the leukemia recurs after 4 months on average and is typically drug-resistant owing to the acquisition of additional mutations. Therefore, the understanding of the underlying mutation mechanism and its potential inhibition appears to be critical for further improvement of treatment strategies of Ph+ ALL and CML. Recent work by our group demonstrated that the oncogenic BCR-ABL1 kinase in Ph+ ALL and blast crisis, but not chronic phase CML, induces expression of a mutator enzyme, termed AID (Activation-induced Cytidine Deaminase). The mutations that confer drug-resistance in Ph+ ALL and blast crisis CML can indeed be explained by activity of the AID enzyme. Additional experiments showed that engineered expression of AID in AID-negative chronic phase CML cells introduces the same mutations that cause drug-resistance in patients with AID-positive Ph+ ALL and CML blast crisis. Based on these observations, we propose four series of experiments to address the following questions: (1) Is the AID enzyme required for drug-resistance in AID-positive Ph+ ALL? To test this hypothesis, we will investigate whether BCR-ABL1-induced leukemia cells from mice carrying a deletion of the AID-gene fail to develop drug-resistance. (2) Does the AID enzyme play a critical role in the progression of chronic phase CML into blast crisis? Chronic phase CML can be treated very successfully for many years, whereas blast crisis represents a final and often fatal stage of the disease. (3) Which are the factors that induce aberrant expression of the AID enzyme in Ph+ ALL and blast crisis CML? The identification of such factors will likely help to understand how expression of this deleterious mutator enzyme can be prevented. (4) Is it possible to target AID-expressing cells by taking advantage of the enzymatic activity of AID? For this approach, we propose to use a precursor-drug that has no effect as such but will become toxic upon AID-mediated conversion. Given that AID-expressing cells are more likely to be drug-resistant than others, we propose a treatment approach that is focused on the AID-expressing leukemia cells.