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. IntroductionChildhood acute lymphoblastic leukemia (ALL) has very diverse genetics, 1 but there is substantial evidence that segregates its development into a prenatal initiation phase followed by later acquisition of other mutations, presumed to be more proximal to diagnosis. 2 This developmental sequence is most clearly defined for ALL in which ETV6-RUNX1 fusion is the prenatal and probable initiating event, but it is also probable to hold for hyperdiploid ALL 3 and other, although not necessarily all, 4 subtypes. Much of the evidence for the developmental sequence of acquired genetic events in ALL has been derived from the study of monozygotic twins that are concordant or discordant for ALL. 5 In both such instances, the initiating lesion and premalignant clone is shared by the twins as a consequence of intraplacental vascular anastomoses and blood cell chimerism. The twin data are endorsed by backtracking of prenatal-initiating genetic lesions in the archived blood spots, or Guthrie cards, of patients with ALL. 6,7 BCR-ABL1 (Philadelphia chromosome positive [Ph ϩ ]) ALL is a relatively infrequent (ϳ 5%) subtype of pediatric ALL. It traditionally had a poor prognosis with conventional chemotherapy, 8 but the introduction of the selective kinase inhibitor imatinib has significantly improved early event-free survival. 9 IKZF1 deletions are common (ϳ 85%) in Ph ϩ ALL 10,11 and in high-risk (HR) ALL without BCR-ABL1 fusion (ϳ 28%) 12 and are associated with adverse outcome. 12,13 The developmental timing or sequence of these "coupled" genetic events in Ph ϩ ALL is however unknown.We report here 2 identical twin pairs, one concordant, the other discordant, for Ph ϩ ALL. In...

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