The biology of relapsed acute lymphoblastic leukemia: opportunities for therapeutic interventions

Abstract

Although great strides have been made in the improvement of outcome for newly diagnosed pediatric acute lymphoblastic leukemia because of refinements in risk stratification and selective intensification of therapy, the prognosis for relapsed leukemia has lagged behind significantly. Understanding the underlying biological pathways responsible for drug resistance is essential to develop novel approaches for the prevention of recurrence and treatment of relapsed disease. High throughput genomic technologies have the potential to revolutionize cancer care in this era of personalized medicine. Using such advanced technologies, we and others have shown that a diverse assortment of cooperative genetic and epigenetic events drive the resistant phenotype. Herein, we summarize results using a variety of genomic technologies to highlight the power of this methodology in providing insight into the biological mechanisms that impart resistant disease.

Figure 1. Model of evolution of relapsed disease

A preleukemic stem cell (LSC, light blue) gives rise to frank ALL (dark blue cells). Intrinsically drug resistant clones (red) may be present at diagnosis at low levels. However, LSCs and other subclones may survive initial treatment and acquire additional lesions that result in acquired drug resistance. Rarely, relapse clone is genetically distinct from that at diagnosis (second malignancy).

Figure 2. NCoR complex mutations identified in relapsed ALL

Schematic illustrating mutations, copy number abnormalities, differential methylation, and altered gene expression in protein components of the NCoR complex. Only those NCoR complex proteins that have been found to be altered at relapse are shown here.

Figure 3. Schematic representation of purine nucleoside analogue therapy during ALL treatment

SR (standard risk) and HR (high risk) back bones are shown above with height of the bars representing relative amounts of 6MP/6TG used during treatment cycles. The solid line represents theoretical outgrowth of NT5C2 mutant clones during maintenance therapy leading to relapse disease.