Monitoring of childhood ALL usingBCR-ABL1genomic breakpoints identifies a subgroup with CML-like biology.
We used the genomic breakpoint betweenBCRandABL1genes 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 ofIKZF1deletion, 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-ABL1variants in the consecutive cohorts) had significantly (>1 log) higher levels ofBCR-ABL1fusion than Ig/TCR rearrangements and/orIKZF1deletion. We performed cell sorting of the diagnostic material and assessed the frequency ofBCR-ABL1-positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored theBCR-ABL1fusion in patients with discrepant MRD results. The multilineage involvement of theBCR-ABL1-positive clone demonstrates that in some patients diagnosed withBCR-ABL1-positive ALL, a multipotent hematopoietic progenitor is affected by theBCR-ABL1fusion. These patients haveBCR-ABL1-positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity ofBCR-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-likeBCR-ABL1-positive ALL.
Childhood Leukemia Investigation Prague (CLIP) and.|Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Lenka
L
Hovorkova
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.
Marketa
M
Zaliova
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Nicola C
NC
Venn
Department of Pediatrics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Kirsten
K
Bleckmann
Gennet, Center for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.
Marie
M
Trkova
Childhood Leukemia Investigation Prague (CLIP) and.|Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Eliska
E
Potuckova
Childhood Leukemia Investigation Prague (CLIP) and.|Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Martina
M
Vaskova
Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Jana
J
Linhartova
Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Katerina
K
Machova Polakova
Childhood Leukemia Investigation Prague (CLIP) and.|Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Eva
E
Fronkova
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Walter
W
Muskovic
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Jodie E
JE
Giles
Blood and Marrow Transplant Services, Children's Hospital at Westmead, Sydney, NSW, Australia; and.
Peter J
PJ
Shaw
Department of Pediatrics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Gunnar
G
Cario
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.|School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
Rosemary
R
Sutton
Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.|University Hospital Motol, Prague, Czech Republic.
Jan
J
Stary
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.
Jan
J
Trka
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.
Jan
J
Zuna
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D015894:Genome, Human; D006410:Hematopoiesis; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000235:genetics*; D007958:Leukocyte Count; D018365:Neoplasm, Residual / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D016896:Treatment Outcome
C497239:IKZF1 protein, human; D011948:Receptors, Antigen, T-Cell; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl