Leukemia, Acute Lymphoblastic, Susceptibility To, 3
A number sign (#) is used with this entry because of evidence that susceptibility to acute lymphoblastic leukemia-3 (ALL3) is conferred by heterozygous mutation in the PAX5 gene (167414) on chromosome 9p13.
For a general phenotypic description and a discussion of genetic heterogeneity of acute lymphoblastic leukemia, see 613065.
Clinical FeaturesShah et al. (2013) reported 2 unrelated families in which multiple individuals in several generations had childhood onset of B-cell acute lymphoblastic leukemia (B-ALL). Relapse was common. One of the families was of Puerto Rican descent and the other was of African American descent.
Gu et al. (2019) characterized 2 subtypes of B-ALL, PAX5alt (PAX5-altered) and PAX5 pro80 to arg (P80R), that are defined by PAX5 alterations (see MOLECULAR GENETICS). The median ages at diagnosis for subjects in the P80R and PAX5alt groups were 22.0 years and 15.4 years, respectively. Subjects with P80R and PAX5alt subtypes had median presenting white blood cell counts of 13.0 x 10(-9) per liter and 16.9 x 10(-9) per liter, respectively, and were more likely to be male (65.9% and 68.9%). Positive minimal residual disease at the end of induction was detected in 7.2% and 29.4% of P80R and PAX5alt cases, respectively. In children treated in the Children's Oncology Group AALL0232 study of National Cancer Institute (NCI) high-risk B-ALL, the outcome was intermediate for both P80R (5-year event-free survival 75.0 +/- 14.2%, overall survival 75.0 +/- 14.2% in 8 evaluable cases) and PAX5alt (event-free survival 71.5 +/- 7.0%, overall survival 75.7 +/- 6.6% in 46 evaluable cases) compared with other favorable risk subtypes. Adults with PAX5 P80R ALL (15 of 288 evaluable cases) had intermediate and superior outcomes (event-free survival 63.0 +/- 13.3%, overall survival 61.9 +/- 13.4%) compared with those subjects with PAX5alt (event-free survival 32.2 +/- 9.4%, overall survival 42.1 +/- 10.2%, 27 evaluable cases).
InheritanceThe transmission pattern of B-cell ALL in the families reported by Shah et al. (2013) was consistent with autosomal dominant inheritance and incomplete penetrance.
Molecular GeneticsIn affected members of 2 unrelated families with childhood onset of B-cell acute lymphoblastic leukemia, Shah et al. (2013) identified a heterozygous germline missense mutation in the PAX5 gene (G183S; 167414.0001). The mutation was found by exome sequencing and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. The mutation segregated with the disorder, but there were several unaffected obligate carriers, suggesting incomplete penetrance. All available leukemic samples showed loss of chromosome 9p through the formation of an isochromosome of 9q (i(9)(q10)) or dicentric chromosomes, both resulting in loss of the wildtype PAX5 allele and retention of the mutant allele. Haplotype analysis suggested that the mutation arose independently in each family. In vitro functional expression studies showed that the mutant G183S protein had normal subcellular localization, but reduced transcriptional activation compared to wildtype, indicating partial loss of function. Transcriptional profiling of mouse cells expressing the mutation showed reduced expression of genes activated by PAX5 in pro-B cells and mature B cells. However, the effect of the G183S mutant was not as severe as that observed for complete loss-of-function alleles. The findings suggested that this partial hypomorphic allele is tolerated as a germline allele and that additional somatic genetic events further reducing PAX5 activity are required to establish the leukemic clone. No germline PAX5 mutations were detected in 39 families with a history of 2 or more cases of cancer, although 1 familial case of ALL harbored a somatic dic(9;20)(p11;q11.1) alteration and a somatic PAX5 variant.
Using integrated genomic analysis of leukemic cells from 1,988 childhood and adult cases of B-ALL, Gu et al. (2019) described a revised taxonomy of B-ALL incorporating 23 subtypes. Two subtypes were characterized by distinct gene expression profiles and different types of PAX5 alterations. One, PAX5alt (PAX5-altered), accounted for 148 (7.4%) of cases and had diverse PAX5 alterations including rearrangements, intragenic amplifications, or mutations. Children in this subtype were more commonly classified as high risk rather than standard risk (63 vs 17, respectively) according to NCI criteria. In the PAX5alt group, 57 cases (38.5%) harbored PAX5 rearrangements involving 24 partner genes, the most common of which was PAX5-ETV6 (600618) in 19 cases. Forty-six (31%) of PAX5alt group cases harbored nonsilent PAX5 sequence mutations, compared with 79 (4.4%) of other B-ALL cases, excluding cases defined by PAX5 mutation pro80 to arg (P80R). A distinct second PAX5 subtype was defined by the P80R variant (615545.0002), which was present in all 44 cases compared with 4 of 1,944 other B-ALL cases (0.2%). In 30 cases, the P80R mutation was hemizygous or homozygous, owing to deletion of the wildtype PAX5 allele or copy-neutral loss of heterozygosity. Of the remaining 14 cases with heterozygous PAX5 P80R-encoding alterations, 7 harbored a second frameshift, 2 a nonsense, and 4 a deleterious missense PAX5 mutation. The 4 of remaining 1,944 cases that harbored the P80R mutation were heterozygous with preservation of a wildtype PAX5 allele and had similar gene expression profiles to those of other subtypes, in agreement that biallelic PAX5 mutations, including P80R, are a hallmark of this subtype.