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Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A

Leukemia volume 28, pages 1136–1138 (2014)Cite this article

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A single-nucleotide polymorphism (SNP) in PAX5 leading to an amino-acid change in the octapeptide domain at position c.547G>A (p.Gly183Ser) has recently been described to confer an inherited susceptibility for childhood pre B-ALL.1 This susceptibility was transmitted autosomal dominant in two independent families with variable penetrance and aberrations of chromosomal part 9p resulting in loss of the wild-type (wt) PAX5 allele occurruring simultaneously in the leukemic cells.

The PAX5 c.547G>A was transmitted from the grandfather to the fathers and subsequently to five out of seven children, three of whom developed pre B-ALL. The mothers of the affected children are neither related to the fathers nor to each other and originate from different ethnical backgrounds. The broader family history confers no susceptibility to leukemia. Hence, the predisposition to pre B-ALL follows an autosomal dominant mendelian transmission with variable penetrance. Three children are affected with pre B-ALL in the family, two siblings (C6 and C7) and one cousin (C3) (Figure 1a). Leukemia occurred at the age of 55 months (C3), 16 months (C6) and 21 months (C7). C3 suffered from a relapse 8 years after the first diagnosis. The immunophenotype showed expression of CD19, CD10 and CD20, molecular genetic analysis was negative for TEL/AML1, MLL and BCR/ABL. However, all leukemic probes had an abnormal karyotype affecting the 9p region as observed in the two families published by Shah et al.1 C3L showed dic (9;12)(p11-13;p11), which was conserved in the relapse karyotype, C6L del(9)(p13;p22) and C7L i(9)(q10). Fluorescence in situ hybridization (FISH) analysis using the FISH probe for 9p21 (Abbott, Abbott Park, IL, USA) that includes the CDKNA2 locus was performed showing CDKN2A deletion in the leukemic samples of C3, C6 and C7. Microsatellite polymorphic marker analysis located on chromosome 9 between 19.13 MB and 37.2 MB (hg19) demonstrated a shared haplotype in the three affected children, their fathers and two of their siblings.

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References

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Authors and Affiliations

  1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany

    F Auer, M Gombert, P Husemann, S Ginzel, A Borkhardt & J Hauer

  2. Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany

    F Rüschendorf

  3. Helmholtz Centre for Infection Research, Braunschweig, Germany

    P Husemann

  4. Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany

    S Ginzel

  5. Functional Genomics and Childhood Leukemia Research, Sheba Medical Center Tel-Hashomer, Ramat Gan, Israel

    S Izraeli

  6. Department of Human Molecular Genetics and Biochemsitry, Tel Aviv University, Tel Aviv, Israel

    S Izraeli

  7. Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    M Harit, M Weintraub & P Stepensky

  8. Department of Human Genetics & Metabolic Diseases,

    O Y Weinstein & I Lerer

  9. Hadassah Medical Center, Ein Kerem, Jerusalem, Israel

    O Y Weinstein & I Lerer

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  1. F Auer
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Correspondence to J Hauer.

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Auer, F., Rüschendorf, F., Gombert, M. et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia 28, 1136–1138 (2014). https://doi.org/10.1038/leu.2013.363

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