A Recurrent Germline PAX5 Mutation Confers Susceptibility to Pre-B Cell Acute Lymphoblastic Leukemia

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.

Citing Articles

Immune training enhances anti-viral responses and improves outcomes in Pax5 mice susceptible to chronic infection.

Lu Z, Stencel O, Liu W, Vasileiou E, Xu H, Pandey P EMBO Mol Med. 2025; .

PMID: 40082582 DOI: 10.1038/s44321-025-00208-4.

Comparative Profiling of Regulatory Modules as a Tool for Identifying the Transcription Factor Network Linked to Leukemogenesis.

Subramanian S, Phongbunchoo Y, Cauchy P, Ramamoorthy S Methods Mol Biol. 2025; 2909:179-209.

PMID: 40029523 DOI: 10.1007/978-1-0716-4442-3_13.

with Mycovirus as an Etiologic Factor for Acute Leukemias in Susceptible Individuals: Evidence and Discussion.

Tebbi C, Sahakian E, Shah B, Yan J, Mediavilla-Varela M, Patel S Biomedicines. 2025; 13(2).

PMID: 40002901 PMC: 11853382. DOI: 10.3390/biomedicines13020488.

AI learns from chromatin data to uncover gene interactions.

Brozek A, Theodoris C Nature. 2025; 637(8047):799-800.

PMID: 39779986 DOI: 10.1038/d41586-024-04107-5.

A foundation model of transcription across human cell types.

Fu X, Mo S, Buendia A, Laurent A, Shao A, Alvarez-Torres M Nature. 2025; 637(8047):965-973.

PMID: 39779852 PMC: 11754112. DOI: 10.1038/s41586-024-08391-z.

References

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

Cobaleda C, Jochum W, Busslinger M . Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature. 2007; 449(7161):473-7. DOI: 10.1038/nature06159. View

Revilla-I-Domingo R, Bilic I, Vilagos B, Tagoh H, Ebert A, Tamir I . The B-cell identity factor Pax5 regulates distinct transcriptional programmes in early and late B lymphopoiesis. EMBO J. 2012; 31(14):3130-46. PMC: 3400013. DOI: 10.1038/emboj.2012.155. View

Lin M, Wei L, Sellers W, Lieberfarb M, Wong W, Li C . dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics. 2004; 20(8):1233-40. DOI: 10.1093/bioinformatics/bth069. View

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View

Lundblad A, Steller R, KABAT E, HIRST J, WEIGERT M, Cohn M . Immunochemical studies on mouse myeloma proteins with specificity for dextran or for levan. Immunochemistry. 1972; 9(5):535-44. DOI: 10.1016/0019-2791(72)90063-8. View

Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L . The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013; 45(3):242-52. PMC: 3919793. DOI: 10.1038/ng.2532. View

Zhang J, Mullighan C, Harvey R, Wu G, Chen X, Edmonson M . Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011; 118(11):3080-7. PMC: 3175785. DOI: 10.1182/blood-2011-03-341412. View

Venkatraman E, Olshen A . A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics. 2007; 23(6):657-63. DOI: 10.1093/bioinformatics/btl646. View

10.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

11.

Mullighan C . Single nucleotide polymorphism microarray analysis of genetic alterations in cancer. Methods Mol Biol. 2011; 730:235-58. DOI: 10.1007/978-1-61779-074-4_17. View

12.

Mullighan C, Miller C, Radtke I, Phillips L, Dalton J, Ma J . BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008; 453(7191):110-4. DOI: 10.1038/nature06866. View

13.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

14.

Pounds S, Cheng C, Mullighan C, Raimondi S, Shurtleff S, Downing J . Reference alignment of SNP microarray signals for copy number analysis of tumors. Bioinformatics. 2008; 25(3):315-21. PMC: 2639073. DOI: 10.1093/bioinformatics/btn624. View

15.

Cai Y, Brophy P, Levitan I, Stifani S, Dressler G . Groucho suppresses Pax2 transactivation by inhibition of JNK-mediated phosphorylation. EMBO J. 2003; 22(20):5522-9. PMC: 213790. DOI: 10.1093/emboj/cdg536. View

16.

Irizarry R, Hobbs B, Collin F, Beazer-Barclay Y, Antonellis K, Scherf U . Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-64. DOI: 10.1093/biostatistics/4.2.249. View

17.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

18.

Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas O . Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia. 2008; 23(1):134-43. DOI: 10.1038/leu.2008.306. View

19.

Czerny T, Busslinger M . DNA-binding and transactivation properties of Pax-6: three amino acids in the paired domain are responsible for the different sequence recognition of Pax-6 and BSAP (Pax-5). Mol Cell Biol. 1995; 15(5):2858-71. PMC: 230517. DOI: 10.1128/MCB.15.5.2858. View

20.

Mullighan C, Downing J . Global genomic characterization of acute lymphoblastic leukemia. Semin Hematol. 2008; 46(1):3-15. PMC: 2834786. DOI: 10.1053/j.seminhematol.2008.09.005. View