The Role and Regulation of Quiescence in Acute Lymphoblastic Leukaemia

There are ˜3,000 children, as well an additional ˜7,000 adults, diagnosed with acute lymphoblastic leukaemia (ALL) each year in the USA. This makes ALL the most common cancer diagnosed in children. It represents ˜25% of paediatric cancer diagnoses. With current therapy, most patients achieve a complete remission and many are cured. However, the prognosis remains quite poor for the ˜15–20% of children who suffer a relapse of their ALL. Improved outcomes for these relapsed patients will require either more efficacious salvage therapies or improved initial therapy that prevents ALL relapse. Thus, understanding the mechanisms by which a small population of leukaemia cells can escape therapy and contribute to relapse often months or years later is critical for improving ALL outcomes. Herein, we will review emerging clinical and laboratory research that suggest quiescence, or dormancy, is an important cellular mechanism that enhances ALL chemo-resistance and persistence, and ultimately contributes to disease relapse. Furthermore, the mechanisms that regulate this balance between leukaemia quiescence and proliferation are beginning to be elucidated and will provide new knowledge about leukaemia biology. Finally, these observations support the need for and feasibility of therapeutically targeting these quiescent, chemo-resistant ALL cells by either exploiting metabolic or signalling pathway vulnerabilities unique to quiescent cells, or by causing the release of ALL cells from the protective niche(s) that triggers and maintains ALL quiescence.