Genetic and transcriptional landscape of plasma cells in POEMS syndrome

Nagao, Yuhei; Mimura, Naoya; Takeda, June; Yoshida, Kenichi; Shiozawa, Yusuke; Oshima, Motohiko; Aoyama, Kazumasa; Saraya, Atsunori; Koide, Shuhei; Rizq, Ola; Hasegawa, Yoshinori; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Nishijima, Dai; Isshiki, Yusuke; Kayamori, Kensuke; Kawajiri-Manako, Chika; Oshima-Hasegawa, Nagisa; Tsukamoto, Shokichi; Mitsukawa, Shio; Takeda, Yusuke; Ohwada, Chikako; Takeuchi, Masahiro; Iseki, Tohru; Misawa, Sonoko; Miyano, Satoru; Ohara, Osamu; Yokote, Koutaro; Sakaida, Emiko; Kuwabara, Satoshi; Sanada, Masashi; Iwama, Atsushi; Ogawa, Seishi; Nakaseko, Chiaki

doi:10.1038/s41375-018-0348-x

Cited by 29 publications

(35 citation statements)

References 45 publications

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“…Translocations and deletion of chromosome 13 have been described . Whole exome sequencing, targeted sequencing, and RNA sequencing of 11 patients with POEMS revealed 20 mutations in 7 recurrently mutated genes: KLHL6, LTB, EHD1, EML4, HEPHL2, HIPK2, and PCDH10 …”

Section: Disease Overviewmentioning

confidence: 99%

POEMS Syndrome: 2019 Update on diagnosis, risk‐stratification, and management

2019

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Disease Overview: Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. Diagnosis: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. Risk Stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR. Risk-Adapted Therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

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Section: Disease Overviewmentioning

confidence: 99%

POEMS Syndrome: 2019 Update on diagnosis, risk‐stratification, and management

2019

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“…5,6 We also found two patients with IGLV1-36 variable gene, and this gene could potentially be a new IGLV1 gene associated with POEMS syndrome, since it is known as a paralog of IGLVλ1-44 gene 29,12 and contains the consensus sequence VNWYQ in the FR2 domain. Accordingly, an IGLV1-36 sequence associated with POEMS syndrome was recently found by RNAseq in the series of Nagao et al 30 Another hypothesis could be that the LC hypermutations that appear during B cell response could be responsible for the assignment to an IGLV1-36 derived gene in place of the IGLV1-44 one. In any case, the association of this new λ V domain with POEMS syndrome remains to be confirmed with more sequencing data from POEMS patients.…”

Section: Resultsmentioning

confidence: 95%

“…34 However, this hypothesis was refuted in a recent study showing that BM PCs of POEMS patients do not produce more VEGF-A as compared to MGUS ou MM PCs. 30 Given the low level of BM infiltration by monoclonal PCs in POEMS patients, these controversies will likely be resolved by next generation cytometry analysis or single cell transcriptomic. One hypothesis is that the monoclonal λ LC could act as a paracrine or endocrine factor, that could activate the secretion of VEGF-A in cells/tissues.…”

Section: Resultsmentioning

confidence: 99%

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Bender

Javaugue

Saintamand

et al. 2019

Preprint

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POEMS syndrome is a rare multisystem disease due to an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected, due to the highly restrictive usage of two λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ + monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid and specific tool to detect low-abundance PC clones in BM, and assign them to POEMS syndrome, with all the consequences for therapeutic options hereby.

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“…Recently Nagao et al performed molecular analysis of plasma cells from patients with POEMS syndrome by whole exome sequencing, targeted sequencing, and RNA sequencing using NGS, and compared the results with those from patients with multiple myeloma and MGUS. In the studied sample, 20 mutations in 7 recurrently mutated genes (KLHL6, LTB, EHD1, EML4, HEPHL2, HIPK2, and PCDH10) were found 40 . Notably, somatic mutations more common in multiple myeloma involving RAS, NF‐kB and MYC pathways were not found in POEMS samples, suggesting a different pathogenic evolution from multiple myeloma 41 .…”

Section: Monoclonal Gammopathies Of Neurological Significancementioning

confidence: 87%

“…Instead, when there is a disseminated bone marrow involvement even with a low plasma cell count treatment is borrowed by multiple myeloma and/or AL amyloidosis 34‐36 . The current gold standard treatments for POEMS syndrome rely either on low dose or high dose melphalan‐based conditioning chemotherapy followed by autologous stem cell transplantation, that showed good hematologic control (more than 80% of hematological remissions 48 ), and neurological response with clinical and also neurophysiological improvement of neuropathy in almost all patients, and good survival 33‐46‐48 . The immunomodulating and anti‐angiogenetic agent lenalidomide showed encouraging results either in treatment naive and relapsed patients 49‐51 .…”

Section: Monoclonal Gammopathies Of Neurological Significancementioning

confidence: 99%

From pathogenesis to personalized treatments of neuropathies in hematological malignancies

Briani

Visentin

Cerri³

et al. 2020

J Peripheral Nervous Sys

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The peripheral nervous system may be involved at any stage in the course of several hematological diseases, the most common being monoclonal gammopathies (of undetermined significance or malignant) or lymphomas. The underlying pathogenic mechanisms are different and therapies aim at targeting the dangerous either B‐cell or plasma cell clones. Recently, high‐throughput technologies, and next‐generation sequencing have increased our knowledge of hematological diseases pathogenesis by the identification of somatic mutation affecting pivotal signaling pathways. Accordingly, new target therapies are used that may also be borrowed for treatment of neuropathies in hematological diseases.

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Genetic and transcriptional landscape of plasma cells in POEMS syndrome

Cited by 29 publications

References 45 publications

POEMS Syndrome: 2019 Update on diagnosis, risk‐stratification, and management

POEMS Syndrome: 2019 Update on diagnosis, risk‐stratification, and management

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

From pathogenesis to personalized treatments of neuropathies in hematological malignancies

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