Abstract
Introduction
Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease caused by various genetic alterations. Some prognosis-associated chromosomal aberrations and gene mutations such as t(8;21), inv(16), monosomy 7, and FLT3-ITD have been adopted for risk stratification. Although treatment outcomes have improved via stratification therapy, relapse and mortality are still observed in 40% and 30% patients, respectively. Patients with an intermediate risk with no favorable or recurrent factors are considered to exhibit varied biology and outcomes. Further studies are warranted to evaluate the accuracy of prognosis in these patients.
Methods
Among 369 patients with de novo AML participated in the Japanese AML-05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group during 2006-2010, 77 patients including 59 with normal karyotype-AML (NK-AML) and 18 with complex karyotype-AML (CK-AML) were enrolled. Targeted sequencing was performed using a 343-gene custom panel and next-generation sequencer. Reportedly, these 343 genes are associated with hematopoietic malignancy or solid tumor pathogenesis. Correlations among gene mutations, other cytogenetic alterations, and clinical characteristics were investigated.
Results
In all, 187 mutations in 61 genes (average: 2.42 mutations/patient) were detected, and 72 patients (93%) had at least one genetic mutation.
Among patients with NK-AML, 51 (86%) had one of the following driver mutations: FLT3-ITD, KMT2A-PTD, CEBPA, or NPM. Interestingly, internal tandem duplication (ITD) of BCOR (BCOR-ITD) was detected along with several novel ITDs in patients with unclear AML pathogenesis.
Among patients with CK-AML, the following mutations regarding myelodysplastic syndrome (MDS) pathogenesis were detected: TP53: 3 (17%), JAK2: 2 (11%), ASXL1: 2 (11%), U2AF1: 1 (7%), SF3A1: 1 (7%), RUNX1: 2 (11%), and BCOR/BCORL1: 3 (17%). Consequently, 15 of 18 (83%) patients with CK-AML had some genetic mutations related to MDS. Eight types of transcription factor mutations and five of epigenetic factor mutations were detected in 10 patients. Eight of these (80%) relapsed or died. Three RUNX1 rearrangements (RUNX1-CBFA2T2, RUNX1-CBFA2T3, and RUNX1-FNBP1) and other fusions (PICALM-MLL10 and MYB-GATA1) were detected in patients with CK-AML. Interestingly, these patients had a low transcription factor or epigenetic factor mutation number; all of them survived without relapse.
Discussion
We detected several novel ITDs other than FLT3-ITD in patients with NK-AML. KIT-ITD was reported in adult and pediatric patients with AML; BCOR-ITD was linked to the pathogenesis of pediatric clear-cell sarcoma of the kidney. However, the clinical significance of ITDs, other than FLT3-ITD, has not been revealed in AML, for which further studies are being planned.
This study identified the characteristic genetic background (i.e., MDS) in patients with CK-AML. Most patients with CK-AML (17/18; 94%) were diagnosed as AML with MDS related changes, according to World Health Organization classification. Fifteen of those (88%) had genetic mutations related to MDS pathogenesis. Furthermore, several RUNX1 rearrangements were detected in patients with CK-AML. Reportedly, RUNX1-CBFA2T2 and RUNX1-CBFA2T3 are recurrent fusions in adult AML. Particularly, RUNX1-CBFA2T3 has a gene expression profile similar to that of RUNX1-RUNX1T1, which may explain the favorable outcome in patients with such rearrangements.
Despite the small sample size of this study, the findings indicate two major subgroups of pediatric CK-AML: 1) CK-AML with MDS-related genetic mutations (i.e., transcription factor and epigenetic factor mutations) linked to poor outcomes and 2) CK-AML with few of these mutations and with fusion genes (e.g., RUNX1) linked to favorable outcomes.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
