Sex-biased<i>ZRSR2</i>mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Togami, Katsuhiro; Chung, Sun Sook; Madan, Vikas; Kenyon, Christopher M.; Cabal-Hierro, Lucía; Taylor, Justin; Kim, Sunhee S.; Griffin, Gabriel K.; Ghandi, Mahmoud; Li, Jia; Li, Yvonne Y.; Angelot‐Delettre, Fanny; Biichlé, Sabéha; Seiler, Michael; Buonamici, Silvia; Lovitch, Scott B.; Louissaint, Abner; Morgan, Elizabeth A.; Jardin, Fabrice; Piccaluga, Pier Paolo; Weinstock, David M.; Hammerman, Peter S.; Yang, Henry; Konopleva, Marina; Pemmaraju, Naveen; Garnache‐Ottou, Francine; Abdel‐Wahab, Omar; Koeffler, H. Phillip; Lane, Andrew A.

doi:10.1101/2020.10.29.360503

Cited by 16 publications

(37 citation statements)

References 69 publications

(85 reference statements)

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“…Summerer et al [ 28 ] analyzed 1367 mutations in 1210 genes in 21 BPDCN cases and found mutations in SRSF2 in 7 (33%), SF3B1 in 2 (10%), U2AF1 in 2 (10%), and ZRSR2 in 2 (10%) cases. Loss-of-function mutations in ZRSR2 have been shown to impair plasmacytoid dendritic cell activation and apoptosis after inflammatory stimuli, thus may impair immunity and predispose to leukemic transformation [ 29 ]. The presence of frequent mutations of RNA splicing factor may result in impairment of RNA splicing and defective assembly of gene transcripts, which could contribute, at least in part, to the disruption of signaling pathways involved in plasmacytoid dendritic cell maturation and thus BPDCN tumorigenesis.…”

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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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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“…Consistently, Yoshida et al demonstrated that nonsense or frameshift mutations in ZRSR2 causing either a premature truncation or a large structural change of the protein, leading to loss-of-function are found exclusively among men and not women [ 42 ]. More recently in a pre-print, Togami et al reported that loss-of-function ZRSR2 mutations are enriched in blastic plasmacytoid dendritic cell neoplasm, a rare leukemia with a three times higher incidence among men and almost all these mutations occur in men [ 43 ].…”

Section: Hypothesized Biologic Mechanisms Implicated In the Gendermentioning

confidence: 99%

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology

Karantanos

Jain

Moliterno

et al. 2021

IJMS

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Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of transformation to acute leukemia compared to women across neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap neoplasms, and CML. More recent studies evaluating the genomic profile of patients with these neoplasms demonstrated a male predominance for mutations in high-risk genes including ASXL1, U2AF1, SRSF2 and ZRSR2. The understanding of the underlying biology is limited but a number of hypotheses have been developed and are currently being investigated. This review summarizes the current knowledge about sex-related differences in the clinical outcomes and genomic profile of patients with chronic myeloid neoplasms and discusses the hypothesized biologic mechanisms as an attempt to explain these observations.

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“…In this study, we observe increased expression of IFNA response genes in T-cells relative to Tcells in the healthy controls, initially suggesting higher levels of IFNA production by pDC-like tumor cells. However, previous research on BPDCN has shown that pDC-like tumor cells produce lower levels of IFNA relative to pDCs from healthy individuals (44,45). Further, little research has been reported describing the role of TNFA signaling in BPDCN, though studies have shown increased TNFA signaling in the plasma of patients with acute myeloid leukemia (46,47).…”

Section: Discussionmentioning

confidence: 99%

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

DePasquale

Ssozi

Ainciburu

et al. 2021

Preprint

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The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasms (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

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Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Cited by 16 publications

References 69 publications

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

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

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

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