A recurrent heterozygous germline PAX5 mutation segregated with pre-B ALL in two families.
Major finding: A recurrent heterozygous germline PAX5 mutation segregated with pre-B ALL in two families.
Concept: Deletion of chromosome 9p in affected individuals led to loss of the wild-type PAX5 allele.
Impact: Mutations in PAX5 are associated with an inherited pre-B-cell cancer susceptibility syndrome.
Somatic loss-of-function mutations of paired box 5 (PAX5), encoding a B-cell lineage transcription factor, arrest B-cell development and occur in approximately 30% of sporadic precursor B-cell acute lymphoblastic leukemias (pre-B ALL). Shah and colleagues report the identification of a recurrent heterozygous germline PAX5 variant that segregated with pre-B-cell ALL in two unrelated kindreds. The inherited mutation resulted in a glycine-to-serine substitution at amino acid 183 (G183S), an alteration not previously identified in sporadic pre-B ALL until sequencing of PAX5 in over 500 sporadic pre-B ALLs identified G183S and G183V mutations in two additional samples that also exhibited loss of wild-type PAX5 due to deletion of chromosome 9p. The inherited mutation significantly reduced PAX5 transcriptional activity and led to downregulation of PAX5 target genes, though not to the same severity as other known loss-of-function PAX5 mutations in sporadic pre-B ALL. Together with the observations that several unaffected carriers were observed in the two kindreds and that all affected individuals lost the remaining wild-type PAX5 allele in leukemia cells through deletion of chromosome 9p, these findings suggest that a hypomorphic PAX5 allele can be tolerated in the germline but that complete loss of PAX5 function is required for pre-B ALL. No other tumors were recurrent in the two families, suggesting that unlike other syndromes that may predispose to leukemia, the germline mutations of PAX5 are specifically associated with familial pre-B ALL. These findings provide strong evidence that loss of PAX5 is a driving event in pre-B ALL and that inherited mutation of this tumor suppressor gene forms the basis for a hereditary pre-B ALL predisposition syndrome.