TP53Mutations in Hypodiploid Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive neoplasm of B- or T-lymphoid progenitors and is the commonest childhood tumor. ALL comprises multiple subtypes characterized by distinct genetic alterations, with stereotyped patterns of aneuploidy present in many cases. Although alterations of TP53 are common in many tumors, they are infrequent in ALL, with the exception of two ALL subtypes associated with poor outcome: relapsed disease and ALL with hypodiploidy. TP53 alterations are present in almost all cases of ALL with low hypodiploidy and are associated with alterations of the lymphoid transcription factor IKZF2 and the tumor-suppressor gene loci CDKN2A and CDKN2B. Remarkably, more than half of TP53 mutations in low-hypodiploid ALL in children are present in nontumor cells, indicating that low-hypodiploid ALL is a manifestation of Li-Fraumeni syndrome. These findings have profound implications for our understanding of the genetic pathogenesis of hypodiploid ALL, suggesting that alteration of TP53 function may promote the distinctive aneuploidy characteristic of hypodiploid ALL. Moreover, the identification of hypodiploidy mandates offering testing for TP53 mutational status to patients and their relatives, with appropriate counseling and disease surveillance.