Abstract
To define the fusion genes in T/myeloid mixed-phenotype acute leukemia (T/M MPAL), we performed transcriptome sequencing of diagnostic bone marrow samples from 20 adult patients. Our analysis identified a second instance of a recurrent MED14-HOXA9 chimeric gene resulting from the in-frame fusion of exon 23 of MED14 and exon 1 of HOXA9, the first in an adult patient. The MED14-HOXA9 fusion gene was detected in both the diagnostic and relapsed blasts with reverse transcription-polymerase chain reaction and Sanger sequencing. The patient received combined conventional chemotherapy but suffered relapse at 11 months and died of disease progression one year after the initial diagnosis. Our data suggest that MED14-HOXA9 is a cryptic recurrent aberration in T/M MPAL, which might indicate an aggressive clinical course and inferior outcome after conventional chemotherapy. Further studies will be carried out to reveal the effects of the MED14-HOXA9 fusion on the differentiation and proliferation of leukemia stem cells, as well as suitable treatment strategies for this emerging entity.
Highlights
T/myeloid mixed-phenotype acute leukemia (T/M MPAL) is a rare malignancy responsible for approximately 1% of all leukemia cases and is characterized by leukemic blasts presenting both T lineage and myeloid markers [1]
In one patient with a normal karyotype, the MED14-HOXA9 fusion transcript was detected using RNA sequencing: exon 23 of MED14 was fused in frame with exon 1 of HOXA9 (Figure 1A and Supplementary Table 1), which was further confirmed with reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing (Figures 1B, C)
The study of Xiao et al showed that PHF6 mutations were present in all blast compartments regardless of lineage differentiation, implicating that PHF6 was an early mutation in T/M MPAL pathogenesis [9]
Summary
T/myeloid mixed-phenotype acute leukemia (T/M MPAL) is a rare malignancy responsible for approximately 1% of all leukemia cases and is characterized by leukemic blasts presenting both T lineage and myeloid markers [1]. A few patients with T/M MPAL have been identified with recurrent genetic aberrations, such as the t(9;22)(q34.1;q11.2)/BCR-ABL1 and t(v;11q23.3)/KMT2A rearrangements [2]. Using next-generation and transcriptome sequencing, Takahashi and Alexander et al elucidated the genetic and epigenetic heterogeneity of MPAL in a case series [5, 6], but only a few of the patients had T/M MPAL. For a better understanding of the genomic landscape of T/M MPAL, we performed transcriptome sequencing of diagnostic blasts from 20 adult patients with normal karyotype or karyotype. MED14-HOXA9 Rearrangement in T/M MPAL failure and, thereby, detected a cryptic cytogenetic aberration involving chromosomes X and 7 effecting the novel occurrence of a chimeric fusion MED14-HOXA9 in an adult patient
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