ABSTRACT
We performed a retrospective analysis of leukaemic surface antigen expression and genomic data from a total of 100 RUNX1-RUNX1T1-positive paediatric acute myeloid leukaemia (AML) patients enrolled in the Japanese Paediatric Leukaemia/Lymphoma Study Group (JPLSG) AML-05 protocol to determine risk factors for relapse. In univariate analysis, the KIT exon 17 mutation (n = 21) and CD19 negativity (n = 59) were significant risk factors for relapse (P = 0·01). In multivariate analysis, CD19 negativity was the sole significant risk factor for relapse (hazard ratio, 3·09; 95% confidence interval, 1·26-7·59; P < 0·01), suggesting that biological differences between CD19-positive and CD19-negative RUNX1-RUNX1T1 AML patients should be investigated.
Subject(s)
Antigens, CD19/biosynthesis , Core Binding Factor Alpha 2 Subunit/biosynthesis , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/mortality , RUNX1 Translocation Partner 1 Protein/biosynthesis , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/therapy , Male , Survival RateABSTRACT
We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.
Subject(s)
Chromosomes, Human, Pair 21/genetics , Chromosomes, Human, Pair 8/genetics , Core Binding Factor Alpha 2 Subunit , DNA-Binding Proteins , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute , Oncogene Proteins, Fusion , RUNX1 Translocation Partner 1 Protein , Repressor Proteins , Transcription Factors , Translocation, Genetic , Adolescent , Adult , Aged , Child , Core Binding Factor Alpha 2 Subunit/biosynthesis , Core Binding Factor Alpha 2 Subunit/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Oncogene Proteins, Fusion/biosynthesis , Oncogene Proteins, Fusion/genetics , RUNX1 Translocation Partner 1 Protein/biosynthesis , RUNX1 Translocation Partner 1 Protein/genetics , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Survival Rate , Transcription Factors/biosynthesis , Transcription Factors/geneticsABSTRACT
BACKGROUND: The optimal monitoring schedules and cutoff minimal residual disease (MRD) levels for the accurate prediction of relapse at all time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with t(8;21) acute myeloid leukemia (AML). METHODS: RUNX1-RUNX1T1 transcript levels were measured in bone marrow samples collected from 208 patients at scheduled time points after transplantation (1530 samples in total). RESULTS: A total of 92.3% of the requested samples were collected, and 74.0% of patients had complete sample collection. The 1-, 3-, and 6-month RUNX1-RUNX1T1 transcript levels could significantly discriminate between continuous complete remission and a hematologic relapse at 1.5-3, 4-6, and 7-12 months but not at >3, >6, and >12 months, respectively. Over 90% of the 175 patients who were in continuous complete remission had a ≥3-log reduction in RUNX1-RUNX1T1 transcript levels from the time of diagnosis at each time point after transplantation and a ≥4-log reduction at ≥12 months. A <3-log reduction within 12 months and/or a <4-log reduction at ≥12 months was significantly related to a higher 3-year cumulative incidence of relapse (CIR) rate in both the entire cohort and the patients with no intervention after HSCT (58.4 vs. 2.2%, 76.5 vs. 2.0%; all P < 0.0001). Patients who had received a preemptive donor lymphocyte infusion when the increase in RUNX1-RUNX1T1 transcripts was ≤1-log according to the above dual cutoff values had significantly lower 1-year CIR rate after intervention than the patients who had received an infusion when the increase was >1-log (0 vs. 55.0%, P = 0.015). CONCLUSIONS: RUNX1-RUNX1T1 transcripts with a <3-log reduction from diagnosis within 12 months and/or a <4-log reduction at ≥12 months after allo-HSCT could accurately predict relapse and may prompt a timely intervention in patients with t(8;21) AML.
