Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia - PubMed (original) (raw)

Case Reports

Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia

Giovanni Cazzaniga et al. Blood. 2011.

Abstract

The timing and developmental sequence of events for BCR-ABL1(+) acute lymphoblastic leukemia (ALL), usually associated with IKAROS (IKZF1) deletions, are unknown. We assessed the status of BCR-ABL1 and IKZF1 genes in 2 pairs of monozygotic twins, one pair concordant, the other discordant for Philadelphia chromosome positive (Ph(+)) ALL. The twin pair concordant for ALL shared identical BCR-ABL1 genomic sequence indicative of monoclonal, in utero origin. One twin had IKZF1 deletion and died after transplantation. The other twin had hyperdiploidy, no IKZF1 deletion, and is still in remission 8 years after transplantation. In the twin pair discordant for ALL, neonatal blood spots from both twins harbored the same clonotypic BCR-ABL1 sequence. Low level BCR-ABL1(+) cells were present in the healthy co-twin but lacked the IKZF1 deletion present in the other twin's leukemic cells. The twin with ALL relapsed and died after transplantation. The co-twin remains healthy and leukemia free. These data show that in childhood Ph(+) ALL, BCR-ABL1 gene fusion can be a prenatal and possibly initiating genetic event. In the absence of additional, secondary changes, the leukemic clone remains clinically silent. IKZF1 is a secondary and probable postnatal mutation in these cases, and as a recurrent but alternative copy number change is associated with poor prognosis.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Sequence of the BCR-ABL1 rearrangements from twins 1A and 2A at diagnosis. The chromatogram and NCBI nucleotide blasts analysis of the BCR-ABL1 breakpoint DNA sequence with BCR intron 1 (NT_011520, black) and ABL1 intron 1 (NT_035014, red) sequences are shown for twins 1A (A) and 2A (B).

Figure 2

Figure 2

PCR amplification of the genomic BCR-ABL1 rearrangements from twins. (A) Genomic BCR-ABL1 rearrangements from twins 1A and 1B at diagnosis; lanes: 1, marker; 2, diagnosis twin 1A; 3, diagnosis twin 1B; 4 and 5, negative controls; 6, no DNA control. (B) Genomic BCR-ABL1 rearrangements from twin 2A at diagnosis and relapse; lanes: 1, marker; 2, diagnosis twin 2A; 3, relapse twin 2A; 4, no DNA control. (C) Genomic BCR-ABL1 rearrangements from twin 2A and healthy twin 2B (Guthrie specimens); lanes: 1, marker; 2, Guthrie card DNA twin 2A; 3, Guthrie card DNA twin 2B; 4, no DNA control.

Figure 3

Figure 3

Immunostained for CD19AMCA, leukemic cell nucleus stained with DAPI. Probes used include Vysis BCR/ABL1 ES probe (BCR/chromosome 22 = green, ABL1/chromosome 9 = red) Ikarosbiotin-Cy5 = pink. F = BCR-ABL1 fusion.

Figure 4

Figure 4

Copy number analysis of the IKZF1 locus in DNA at diagnosis with the use of CNAG 3.0. The blue lines indicate the mean CNA of 5 contiguous SNPs. The numbers 0, 2, and 4 refer to the genomic copy number. (A-C) The bold arrows point to the IKZF1 locus. (C) The fine dotted arrows indicate the genomic breakpoints (base pair location, NCBI35/Hg17) around the IKZF1 gene. (A) Twin 1A, (B) twin 1B, (C) twin 2A, and (D) twin 1A, IKZF1 sequence.

Similar articles

Cited by

References

    1. Pui C-H, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350(15):1535–1548. - PubMed
    1. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nature Rev Cancer. 2003;3(9):639–649. - PubMed
    1. Maia AT, Tussiwand R, Cazzaniga G, et al. Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood. Genes Chromosomes Cancer. 2004;40(1):38–43. - PubMed
    1. Wiemels JL, Leonard B, Wang Y, et al. Site-specific translocation and evidence of post-natal origin of the t(1;19) E2A-PBX1 translocation in childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2002;99(23):15101–15106. - PMC - PubMed
    1. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003;102(7):2321–2333. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources