ABSTRACT
A large-cohort study (619) of acute lymphoblastic leukemia (ALL) revealed an ETV6/RUNX1 (previously known as TEL/AML1) incidence of 18% in pediatric B-cell precussor ALL, indicating no geographical heterogeinity. Association of CD34-negative phenotype, peak incidence in the 3- to 7-year age group, and a comparatively low frequency of ETV6 homologue loss in ETV6/RUNX1-positive cases were distinct findings in this series. Additional genetic changes, such as ETV6 loss, extra RUNX1, ETV6/RUNX1 duplication, and MLL aberrations in the ETV6/RUNX1-positive group, supported the hypothesis of the ETV6/RUNX1 leukemogenic model that these secondary changes are necessary for leukemogenesis rather than progression of disease. This study disclosed RUNX1 alterations in the ETV6/RUNX1-negative group of BCP-ALL that encourages the investigation of RUNX1 at a large scale with longer follow-up, which will focus on the prognostic importance and the underlying biology of disease.
Subject(s)
Chromosome Aberrations , Core Binding Factor Alpha 2 Subunit/genetics , Oncogene Proteins, Fusion/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , ETS Translocation Variant 6 ProteinABSTRACT
Out of 76 pediatric cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) positive for ETV6/RUNX1 (previously TEL/AML1) resulting from t(12;21), 7 cases revealed coexistence of ETV6/RUNX1 and MLL aberrations. One case of der(21) duplication with ETV6/RUNX1 exhibited a novel MLL translocation variant t(6;11)(p21.1p23;q13q25), with translocation of 3' telomeric MLL and deletion of 5' centromeric MLL. Another case of der(21) duplication with ETV6/RUNX1 showed MLL rearrangement upon Southern blotting. The remaining five ETV6/RUNX1-positive cases had MLL allelic deletion. ETV6/RUNX1 and MLL aberration clone size in these cases was suggestive of ETV6/RUNX1 as an early primary event, originating in the embryonic or infant stage and developing into leukemia by later acquisition of MLL aberration, ETV6 loss, and ETV6/RUNX1 duplication as secondary events. To date, the prognosis has been favorable, which seems to be compatible with ETV6/RUNX1-positive ALL. We conclude that the cases with coexisting ETV6/RUNX1 and MLL aberrations probably exist as a small, hidden group of ETV6/RUNX1-positive BCP-ALL, which invites further investigation, in large series from different populations, to confirm the findings and establish the biological mechanisms and prognostic significance.
Subject(s)
Chromosome Aberrations , Core Binding Factor Alpha 2 Subunit/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Oncogene Proteins, Fusion/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Histone-Lysine N-Methyltransferase , Humans , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classificationABSTRACT
Studies were done to investigate MLL gene aberrations using Conventional Cytogenetics, Southern blotting as well as FISH using a panel of probes on 218 cases which included 206 cases of pediatric/young adult ALL and 12 cases of infantile acute leukemias from Tata Memorial Hospital, India. The incidence of MLL gene rearrangements in acute lymphoblastic leukemia (ALL) was 9.4% which included infants as well as pediatric/young adults. In infantile group which included ALL as well as AML cases, MLL gene rearrangement was very common (75% frequency). Application of metaphase-FISH helped unravel MLL rearrangements not only as a result of translocations but also inversions, insertions, partial deletion, duplications, partial duplication-->self-fusion. Besides age, MLL gene rearrangements showed significant association with hyperleukocytosis, peripheral blood blast percentage and early Pre-B phenotype. Clinical outcome of patients with MLL gene rearrangements revealed unfavorable prognosis.
