CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype

Abstract

• The CBFA2T3-GLIS2 fusion transcript is common in pediatric cytogenetically normal AML and not restricted to FAB M7 subtype.• The CBFA2T3-GLIS2 fusion transcript is associated with poor prognosis in pediatric patients with AML.Pediatric cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous subgroup of myeloid clonal disorders that do not harbor known mutations. To investigate the mutation spectrum of pediatric CN-AML, we performed whole-transcriptome massively parallel sequencing on blasts from 7 CN-AML pediatric patients. In 3 patients we identified a recurrent cryptic inversion of chromosome 16, encoding a CBFA2T3-GLIS2 fusion transcript. In a validation cohort of 230 pediatric CN-AML samples we identified 17 new cases. Among a total of 20 patients with CBFA2T3-GLIS2 fusion transcript out of 237 investigated (8.4%), 10 patients (50%) did not belong to the French-American-British (FAB) M7 subgroup. The 5-year event-free survival for these 20 children was worse than that for the other CN-AML patients (27.4% vs 59.6%; P 5 .01). These data suggest that the presence of CBFA2T3-GLIS2 fusion transcript is a novel common feature of pediatric CN-AML, not restricted to the FAB M7 subtype, predicting poorer outcome. (Blood. 2013;121(17):3469-3472) IntroductionPediatric acute myeloid leukemia (AML) is a molecularly heterogeneous disease that arises from genetic alterations of pathways that regulate self-renewal and myeloid differentiation. While the majority of patients carry recurrent chromosomal translocations, almost 20% of childhood AMLs do not show any recognizable cytogenetic alteration and are defined as cytogenetically normal AML (CN-AML). 1Many genetic abnormalities have been identified in AML with normal karyotype, with the most frequent affecting genes such as NPM1, FLT3, CEBPA, and WT1. 1-5Genome-wide analyses have been used with the aim of determining the full array of genetic lesions of CN-AML. Recent studies have provided new insight into the molecular genetics and biology of AML, confirming both the complexity and the heterogeneity of this disease.6 Novel lesions such as mutations in IDH1 and DNMT3A have been identified. 7,8 However, these alterations are rare in pediatric AML, with IDH1/IDH2 accounting for 2% to 4% of cases 9,10 and DNMT3A not even being found mutated in childhood AML.11 Recently, 2 studies identified a novel recurrent translocation involving CBFA2T3 and GLIS2 in about 30% of children with non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, AML French-American-British [FAB] M7).12,13 Nevertheless, there are many children with CN-AML in whom no genetic abnormality has been detected. The identification of the different genetic profiles characterizing this subgroup is a primary objective to be pursued. To this end, we performed whole-transcriptome massively parallel sequencing of 7 cases of pediatric CN-AML with the aim of identifying recurrent somatic mutations or genomic rearrangements. Subsequently, we validated our findings in a larger cohort of 230 pedi...

Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study.

“…These considerations must certainly be put forward also in our cohort of patients, which, however, did not include any child with acute promyelocytic leukemia or core-binding factor anomalies. As we previously reported, 17 37 HR patients (11% of the whole HR population included in the AIEOP-2002/01 protocol) received neither AUTO-nor ALLO-HSCT at the end of consolidation therapy. These patients had a significantly worse outcome in comparison with those given HSCT.…”

The biology of pediatric acute megakaryoblastic leukemia

“…16 Furthermore, the CBFA2T3-GLIS2 fusion gene conferred a poor prognosis, a finding that has since been confirmed. 16,17,85 This fusion was subsequently reported to also occur at a low frequency in pediatric cytogenetically normal AML. 85 Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, a pathway not previously implicated in AML, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors.…”

“…16,17,85 This fusion was subsequently reported to also occur at a low frequency in pediatric cytogenetically normal AML. 85 Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, a pathway not previously implicated in AML, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. 16 The contribution of BMP signaling to self-renewal in CBFA2T3-GLIS2 modified murine hematopoietic cells has since been confirmed in colony-formation assays utilizing Bmp2 and Bmp4 conditional-knockout marrow (unpublished data).…”

Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia

“…7 In the VHR group, we will allocate children with (1) poor MRD clearance 7 ; (2) WBC count at diagnosis .100 3 10 9 /L in the absence of molecular lesions typical of SR; (3) AML FAB-M7 without t(1;22); (4) complex or monosomal karyotype; (5) FLT3-ITD; and (6) recently detected poor-prognosis molecular lesions. 48,49 The remaining children will be assigned to the HR group. SR patients will be offered chemotherapy-only treatment, while HR children with an HLA-identical sibling available and all VHR children will be offered an allograft.…”