title: Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia.
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.
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Universita di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy. gianni.cazzaniga@hsgerardo.org
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.forename: Luca
authors.initials: L
authors.lastname: Lo Nigro
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Ford
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Elena
authors.initials: E
authors.lastname: Mirabile
authors.forename: Mary
authors.initials: M
authors.lastname: Taj
authors.forename: Susan M
authors.initials: SM
authors.lastname: Colman
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
mesh_terms: D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D017809:Fatal Outcome; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D008297:Male; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D011379:Prognosis; D014178:Translocation, Genetic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl