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Blood. 2017 May 18;129(20):2771-2781. doi: 10.1182/blood-2016-11-749978. Epub 2017 Mar 22.

Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology.

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Childhood Leukemia Investigation Prague (CLIP) and.
Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
University Hospital Motol, Prague, Czech Republic.
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Department of Pediatrics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Gennet, Center for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.
Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Blood and Marrow Transplant Services, Children's Hospital at Westmead, Sydney, NSW, Australia; and.
School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.


We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% [8/32] with minor and 12.5% [1/8] with major-BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion. We performed cell sorting of the diagnostic material and assessed the frequency of BCR-ABL1-positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored the BCR-ABL1 fusion in patients with discrepant MRD results. The multilineage involvement of the BCR-ABL1-positive clone demonstrates that in some patients diagnosed with BCR-ABL1-positive ALL, a multipotent hematopoietic progenitor is affected by the BCR-ABL1 fusion. These patients have BCR-ABL1-positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity of BCR-ABL1-positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like BCR-ABL1-positive ALL.

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