Abnormalities of the der(12)t(12;21) in ETV6-RUNX1 acute lymphoblastic leukemia.
ETV6-RUNX1 fusion [t(12;21)(p13;q22)] occurs in 25% of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is associated with a favorable outcome. Additional abnormalities involving der(21)t(12;21) and nonrearranged chromosome 12 are well characterized but aberrations involving the der(12)t(12;21) have rarely been described. Herein, we describe two novel abnormalities affecting the der(12)t(12;21): a deletion (20/247, 8%) and duplication (10/247, 4%). All 30 patients were under 10 years of age, had a median white blood count of 12.4 × 10(9)/L and 19.2 × 10(9)/L, respectively, with a good outcome. Deletions of der(12)t(12;21) on both sides of the breakpoint were confirmed and mapped: centromeric (12p11.21-12p13.2) and telomeric (21q22.12-21q22.3). The size of these deletions extended from 0.4-13.4 to 0.8-2.5 Mb, respectively. The centromeric deletion encompassed the following genes: LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B. We postulate that this deletion occurs at the same time as the translocation because it was present in all ETV6-RUNX1-positive cells. A second abnormality representing duplication of the reciprocal RUNX1-ETV6 fusion gene was a secondary event, which we hypothesize arose through mitotic recombination errors. This led to the formation of the following chromosome: der(12)(21qter→21q22.12::12p13.2-12p12.3::12p12.3→12qter). Both abnormalities affect the reciprocal RUNX1-ETV6 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis. However, other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations. In conclusion, this study has defined novel abnormalities in ETV6-RUNX1 BCP-ALL, which implicate new genes involved in leukemogenesis.
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
Halima
H
Al-Shehhi
Zoe J
ZJ
Konn
Claire J
CJ
Schwab
Amy
A
Erhorn
Kerry E
KE
Barber
Sarah L
SL
Wright
Alem S
AS
Gabriel
Christine J
CJ
Harrison
Anthony V
AV
Moorman
D002503:Centromere / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D060885:Multiplex Polymerase Chain Reaction; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016615:Telomere / Q000235:genetics; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D017362:Cyclic AMP Response Element-Binding Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054637:Dual-Specificity Phosphatases; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D054639:Mitogen-Activated Protein Kinase Phosphatases; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; C428448:BCL2L14 protein, human; C436291:CDKN1B protein, human; C114097:CREBL2 protein, human; C555475:LRP6 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C439065:DUSP16 protein, human