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

Abstract

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 <i>IKZF1</i> 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 <i>BTG1</i> were significantly enriched in <i>IKZF1</i>-deleted B-cell precursor acute lymphoblastic leukemia (<i>P</i>=0.007). While <i>BTG1</i> deletions alone had no impact on prognosis, the combined presence of <i>BTG1</i> and <i>IKZF1</i> deletions was associated with a significantly lower 5-year event-free survival (<i>P</i>=0.0003) and a higher 5-year cumulative incidence of relapse (<i>P</i>=0.005), when compared with <i>IKZF1</i>-deleted cases without <i>BTG1</i> aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as <i>CDKN2A/B, PAX5, EBF1</i> or <i>RB1</i>, did not affect the outcome of <i>IKZF1</i>-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, <i>Btg1</i>-deficient mice were crossed onto an <i>Ikzf1</i> heterozygous background. We observed that loss of <i>Btg1</i> increased the tumor incidence of <i>Ikzf1^+/-</i> mice in a dose-dependent manner. Moreover, murine B cells deficient for <i>Btg1</i> and <i>Ikzf1^+/-</i> displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify <i>BTG1</i> as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in <i>IKZF1</i>-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.