Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of were significantly enriched in -deleted B-cell precursor acute lymphoblastic leukemia (=0.007). While deletions alone had no impact on prognosis, the combined presence of and deletions was associated with a significantly lower 5-year event-free survival (=0.0003) and a higher 5-year cumulative incidence of relapse (=0.005), when compared with -deleted cases without aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as or , did not affect the outcome of -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, -deficient mice were crossed onto an heterozygous background. We observed that loss of increased the tumor incidence of mice in a dose-dependent manner. Moreover, murine B cells deficient for and displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.