Germline missense NF1 mutation in an elderly patient with a blastic plasmacytoid dendritic cell neoplasm

Szczepaniak, Andrzej; Machnicki, Marcin M.; Gniot, Michał; Pepek, Monika; Rydzanicz, Małgorzata; Płoski, Rafał; Kaźmierczak, Maciej; Stokłosa, Tomasz; Lewandowski, Krzysztof

doi:10.1007/s12185-019-02642-w

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…In another example, guides targeting the E3 ligase Arih2, the E3 ligase substrate Nf1, and the E2 enzyme Ube2f were enriched in DC1s and macrophages and depleted in DC2s ( Figure 1I,J ). This is consistent with and expands on their established roles: Arih2 ubiquitylates substrates of Ube2f, the Nedd8 E2 that mediates neddylation of Cul5-Rbx2 57 , causing degradation of the NF-KB inhibitor Ikbb in DCs 58 , and inactivating mutations in Nf1 lead to uncontrolled cell growth and plasmocytoid DC (pDC) neoplasms 59 .…”

Section: Resultssupporting

confidence: 74%

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

Geiger-Schuller

Eraslan

Kuksenko

et al. 2023

Preprint

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E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the balance of DC1, DC2, migratory DC and macrophage states and a gradient of DC maturation. Family members grouped into co-functional modules that were enriched for physical interactions and impacted specific programs through substrate transcription factors. E3s and their adaptors co-regulated the same processes, but partnered with different substrate recognition adaptors to impact distinct aspects of the DC life cycle. Genetic interactions were more prevalent within than between modules, and a deep learning model, comβVAE, predicts the outcome of new combinations by leveraging modularity. The E3 regulatory network was associated with heritable variation and aberrant gene expression in immune cells in human inflammatory diseases. Our study provides a general approach to dissect gene function.

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Section: Resultssupporting

confidence: 74%

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

Geiger-Schuller

Eraslan

Kuksenko

et al. 2023

Preprint

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“…These findings suggest that TET2 and ASXL1 mutations may represent early events in the pathogenesis of BPDCN, whereas the other mutations are acquired secondarily due to genomic instability and clonal evolution resulting from epigenetic dysregulation. In addition, we identified a few mutations that have not been reported previously in BPDCN, including ETNK1, HNRNPK, HRAS, KDM6A, RAD21 , SF3A1, and SH2B3 , or have only been described in single case reports, including NF1 , NOTCH1 , and SUZ12 [ 12 , 17 , 18 ]. Similar to ASXL1 and TET2 mutations, most of these mutations, such as ZRSR2 (3/5), DNMT3A (3/7), IKZF1 (2/3), ETV6 (2/4), NOTCH1 (1/2), KDM6A (1/1), and SH2B3 (1/1) were also frameshift, premature stop, or splice site mutation, with probable loss of function of the encoded proteins.…”

Section: Discussionmentioning

confidence: 99%

Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm

Yin

Pemmaraju

You

et al. 2021

Cancers

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm derived from plasmacytoid dendritic cells. While advances in understanding the pathophysiology of the disease have been made, integrated systematic analyses of the spectrum of immunophenotypic and molecular alterations in real-world clinical cases remain limited. We performed mutation profiling of 50 BPDCN cases and assessed our findings in the context of disease immunophenotype, cytogenetics, and clinical characteristics. Patients included 42 men and 8 women, with a median age of 68 years (range, 14–84) at diagnosis. Forty-two (84%) patients had at least one mutation, and 23 (46%) patients had ≥3 mutations. The most common mutations involved TET2 and ASXL1, detected in 28 (56%) and 23 (46%) patients, respectively. Co-existing TET2 and ASXL1 mutations were present in 17 (34%) patients. Other recurrent mutations included ZRSR2 (16%), ETV6 (13%), DNMT3A (10%), NRAS (10%), IKZF1 (9%), SRSF2 (9%), IDH2 (8%), JAK2 (6%), KRAS (4%), NOTCH1 (4%), and TP53 (4%). We also identified mutations that have not been reported previously, including ETNK1, HNRNPK, HRAS, KDM6A, RAD21, SF3A1, and SH2B3. All patients received chemotherapy, and 20 patients additionally received stem cell transplantation. With a median follow-up of 10.5 months (range, 1–71), 21 patients achieved complete remission, 4 had persistent disease, and 24 died. Patients younger than 65 years had longer overall survival compared to those who were ≥65 years (p = 0.0022). Patients who had ≥3 mutations or mutations in the DNA methylation pathway genes had shorter overall survival (p = 0.0119 and p = 0.0126, respectively). Stem cell transplantation significantly prolonged overall survival regardless of mutation status. In conclusion, the majority of patients with BPDCN have somatic mutations involving epigenetic regulators and RNA splicing factors, in addition to ETV6 and IKZF1, which are also frequently mutated. Older age, multiple mutations, and mutations in the DNA methylation pathway are poor prognostic factors.

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“…As the mutation profile suggests, epigenetic alterations are common in BPDCN, from DNA methylation ( TET2 , IDH1 , IDH2 ) [ 16 , 18 , 19 , 21 , 32 , 38 , 50 , 51 , 54 , 56 , 57 , 77 ], to histone methylation ( ASXL1 , EZH2 ) [ 10 , 16 , 21 , 50 , 51 , 77 ], or chromatin remodeling ( ARID1A , SUZ12 ) [ 16 , 21 , 50 ]. In 2019, Sapienza et al demonstrated that the epigenetic regulatory program was the most significantly undermined in BPDCN, with shared H3K27-acetylated regions and upregulation of cell-cycle genes marked by promoter acetylation [ 50 ].…”

Section: Dysregulated Pathways In Blastic Plasmacytoid Dendritic Cell...mentioning

confidence: 99%

Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells

Renosi

Callanan

Lefebvre

2022

Cancers

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Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.

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Germline missense NF1 mutation in an elderly patient with a blastic plasmacytoid dendritic cell neoplasm

Cited by 6 publications

References 27 publications

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm

Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells

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