In:
Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 171-171
Abstract:
Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) that morphologically resembles abnormal megakaryoblasts. While extremely rare in adults, pediatric cases comprise 4-15% of newly diagnosed AML patients. Clinical outcomes for Down syndrome (DS) patients with AMKL are uniformly excellent, whereas studies on non-DS patients (non-DS-AMKL) are more variable with the majority reporting inferior survival rates compared to other AML subtypes. Furthermore, the recommendation for stem cell transplant (SCT) in first remission for non-DS-AMKL patients is not uniform among pediatric cooperative groups. Previous efforts have identified chimeric oncogenes in non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, MLL gene rearrangements and NUP98-KDM5A. The etiology of 30-40% of cases, however, remains unknown. To better understand the genomic landscape of non-DS-AMKL and its contribution to clinical outcomes, we performed RNA and exome sequencing on specimens from 115 patients compiled from eight institutions and three cooperative groups including 90 pediatric and 25 adult cases. Of the 104 patients for whom RNA was available, 27.8% (5/18) adult and 72% (62/86) pediatric cases carried a high confidence fusion event by RNAseq. The most frequent fusions in the pediatric cohort when combining RNAseq data, cytogenetics and RT-PCR include CBFA2T3-GLIS2 (17/90), MLL r (13/90), NUP98-KDM5A (9/90), and RBM15-MKL1 (9/90). Previously described low frequency fusions identified in this expanded cohort, include a case of NIPBL-HOXB9 and a novel but functionally analogous NIPBL-HOXA9 fusion. Similarly, a case carrying GATA2-HOXA10 was identified, which is functionally equivalent to the GATA2-HOXA9 fusion that has been reported in a single case. Chimeric transcripts not previously described include several fusions involving genes within the HOX cluster (HOTAIRM1-HOXA3, HOXA_AS3-HOXA9, EWSR1-HOXB8, PLEK-HOXA11-AS, and BMP2K-HOXD10 each in a single case). Collectively, fusions involving a HOX cluster gene (HOX r) occurred in 11% of the pediatric cohort. Single Nucleotide Variation (SNV) analysis of exome and RNAseq data on the cohort revealed the presence of truncating GATA1 mutations in one adult and 10 pediatric specimens lacking fusion genes. Patients carrying GATA1 mutations did not have stigmata of DS or evidence of mutant reads in germline DNA, suggesting they are not mosaics. To determine if these fusion events contribute significantly to gene expression patterns, samples with greater than 60% purity were subjected to unsupervised clustering. Confirming the strength of the fusions in altering gene expression signatures, samples clustered according to fusion subtype and were distinct from those carrying GATA1 mutations. Specifically MLL r, HOX r, NUP98-KDM5A, and CBFA2T3-GLIS2 cases formed distinct clusters. When analyzing differentially upregulated genes within these subgroups, HOX r cases demonstrated upregulation of a HOX gene signature. Combined with MLL r and NUP98-KDM5A, chimeric oncogenes also known to upregulate HOX cluster genes, roughly one-third of pediatric non-DS-AMKL patients carry a HOX gene expression program. These cases were distinct from those carrying the CBFA2T3-GLIS2 inversion. HOX genes play a significant role in normal hematopoietic development and data suggests that deregulated expression has a central role in the etiology of several subtypes of acute leukemia, in part through the acquisition of enhanced self-renewal. We evaluated our identified HOXr for their ability to serially replate in murine colony formation assays as a surrogate marker of this characteristic. Confirming their pathogenicity, chimeric transcripts conferred an enhanced ability to replate. We conclude that chimeric transcripts involving HOX cluster genes comprise a distinct subset of pediatric AMKL. Clinical outcome analyses between genomic subgroups of this heterogeneous malignancy may allow us to more effectively risk stratify these patients and determine those that may benefit from SCT in first remission. JdR and CB contributed equally FL, DR, MH-E, MF, CMZ, and TAG co-corresponding authors on behalf of AIEOP, BFM, DCOG, and SJCRH study groups Disclosures Shih: Novartis: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V126.23.171.171
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2015
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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