Opportunities for targeting gene regulatory factors in B-cell acute lymphoblastic leukemia.

Abstract

“ there is intriguing experimental evidence to suggest targeting gene regulatory factors with pharmaceutical agents could be an effective therapeutic strategy for B-ALL. ” Modern chemotherapy regimens have had a profound impact on the prognosis of individuals diagnosed with B-cell acute lymphoblastic leukemia (B-ALL), especially children [1] . However these treatments achieve substantially poorer survival rates in adults, and are associated with significant short- and long-term toxicities. An advanced understanding of the genetic complexity that characterizes B-ALL allows for more precise patient stratification, and reveals disease subtypes that are at a high-risk for treatment relapse [2] . This genetic profiling has also revealed opportunities for the development of targeted therapies. For example, recurrent BCR–ABL1 translocations define a unique subtype of ALL found in 2–4% of pediatric and at least 25% of adult cases. The activity of this oncogene can be effectively inhibited with the tyrosine kinase inhibitor imatinib, with promising clinical results [3] . Intriguingly, many ALL oncogenes include gene fusions and translocations of transcription regulators and other chromatin associated factors (e.g., ETV6–RUNX1 , TCF3–PBX1 , MYC or MLL rearrangements), revealing the disease to be primarily one of disrupted gene expression control. The mechanistic aspects of these oncogenes are incompletely understood, yet remain an active area of research. These factors can unfortunately also often be viewed as intractable for therapeutics development. Yet much recent progress has been made in targeting gene regulatory complexes with small molecule pharmaceutical agents [4] . Additionally, promising preclinical and early clinical data in B-ALL