Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm

Suzuki, Kyogo; Suzuki, Yuka; Hama, Asahito; Muramatsu, Hideki; Nakatochi, Masahiro; Gunji, Masaharu; Ichikawa, Daisuke; Hamada, Masanori; Taniguchi, Rieko; Kataoka, Shinsuke; Murakami, Norihiro; Kojima, Daisuke; Sekiya, Yuko; Nishikawa, Eri; Kawashima, Nozomu; Narita, Atsushi; Nishio, Naomichi; Nakazawa, Yozo; Iwafuchi, Hideto; Watanabe, Kinuyo; Takahashi, Yoshiyuki; M, Ito; Kojima, Seiji; Kato, Seiichi

doi:10.1038/leu.2017.101

Cited by 47 publications

(49 citation statements)

References 15 publications

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“…The mutation is not known to be pathogenic and has not previously been identified somatically. Exome sequencing of bone marrow identified no additional mutations in DDX41 , and none of the previously reported driver mutations in BPDCN were identified . This is in conjunction with previous reporting where no known driver mutations have been identified in five of seven published pediatric BPCDN cases .…”

Section: Description Of Phenotypic Traits and Genetic Resultssupporting

confidence: 85%

“…RNA expression data as transcripts per million is provided in Supporting Information Table 4, and genes previously found to be either up or down‐regulated in pediatric AML are indicated . CXCR4, a downstream target of MYB, has high expression, in conjunction with previous findings in pediatric BPDCN caused by rearrangement of MYB …”

Section: Description Of Phenotypic Traits and Genetic Resultsmentioning

confidence: 99%

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Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Diness

Risom

Frandsen

et al. 2018

Genes Chromosomes & Cancer

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DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.

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Section: Description Of Phenotypic Traits and Genetic Resultssupporting

confidence: 85%

Section: Description Of Phenotypic Traits and Genetic Resultsmentioning

confidence: 99%

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Diness

Risom

Frandsen

et al. 2018

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

show abstract

“…Furthermore, whole exome and targeted sequencing studies have shown recurrent mutations involving TET2 , ASXL1 , and NPM1 . A recurrent MYB rearrangement was identified by RNA sequencing analysis; in this study, an MYB rearrangement was found in all paediatric patients and in 44% of the adults . Although, in most cases, the genetic translocation partner of MYC at the 6p21 locus was not reported, case 4 showed this partner to be SUPT3H .…”

Section: Discussionmentioning

confidence: 54%

An analysis of blastic plasmacytoid dendritic cell neoplasm with translocations involving the MYC locus identifies t(6;8)(p21;q24) as a recurrent cytogenetic abnormality

et al. 2018

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“…Single nucleotide variants (SNVs) and indels presumed as pathogenic have been observed predominantly in genes involved in cell cycle control (eg, ATM , TP53 ), chromatin regulation (eg, ASXL1 , IDH2 , NPM1 , TET2 ), signal transduction (eg, KRAS , NRAS ), splicing (eg, ZRSR2 ) and transcriptional regulation (eg, IKZF1/2/3 , ZEB2 ) . Additionally, cytogenetic studies, most of them performed in the context of case reports, have revealed chromosomal rearrangements involving ALK , ETV6 , EWSR1 , KMT2A ( MLL ), MYB , MYC , and SUPT3H in a handful of cases …”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11] Additionally, cytogenetic studies, most of them performed in the context of case reports, have revealed chromosomal rearrangements involving ALK, ETV6, EWSR1, KMT2A (MLL), MYB, MYC, and SUPT3H in a handful of cases. [12][13][14][15][16][17][18] Even though these studies have uncovered a variety of genetic abnormalities in BPDCN, none of the reported alterations has provided a clear biological rationale behind neither the genesis of the disease nor its clinical behavior. Furthermore, as yet no study has characterized the landscape of genomic rearrangements and CNAs of BPDCN using high resolution NGS.…”

mentioning

confidence: 99%

Whole‐genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

Torres

Cats

Mei

et al. 2019

Genes Chromosomes & Cancer

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease‐specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole‐genome analysis of BPDCN with a special focus on structural genomic alterations by using whole‐genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide‐level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss‐of‐IKZF1 expression pattern. Furthermore, up‐regulation of cellular processes responsible for cell‐cell and cell‐ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.

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Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm

Cited by 47 publications

References 15 publications

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

An analysis of blastic plasmacytoid dendritic cell neoplasm with translocations involving the MYC locus identifies t(6;8)(p21;q24) as a recurrent cytogenetic abnormality

Whole‐genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

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