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<p>WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström’s Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (<i>MYD88</i><sup><i>MUT</i></sup>) and <i>CXCR4</i> (<i>CXCR4</i><sup><i>MUT</i></sup>) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, <i>WNK2</i> is a top dysregulated gene in <i>MYD88</i><sup><i>MUT</i></sup> WM. To study <i>WNK2</i> regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of <i>WNK2</i> emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like <i>MYD88</i><sup><i>MUT</i></sup> WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, <i>WNK2/S-NK1</i>, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of <i>WNK2</i> in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in <i>MYD88</i><sup><i>MUT</i></sup> WM and a novel therapeutic target in hematological and solid tumor oncology.</p><p></p>

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WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström’s Macroglobulinemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Maria Luisa Guerrera,
  • Xia Liu,
  • Nickolas Tsakmaklis,
  • Abigail L. Peachey,
  • Amanda Kofides,
  • John Hatcher,
  • Andres Ramirez Gamero,
  • Alberto Guijosa,
  • Guang Yang,
  • Hao Sun,
  • Shirong Liu,
  • Christopher J. Patterson,
  • Kirsten Meid,
  • Catherine Flynn,
  • Ruben D. Carrasco,
  • Andrew R. Branagan,
  • Shayna R. Sarosiek,
  • Jorge J. Castillo,
  • Kenneth C. Anderson,
  • Nikhil Munshi,
  • Steven P. Treon,
  • Zachary R. Hunter

摘要

WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström’s Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (MYD88MUT) and CXCR4 (CXCR4MUT) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, WNK2 is a top dysregulated gene in MYD88MUT WM. To study WNK2 regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of WNK2 in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in MYD88MUT WM and a novel therapeutic target in hematological and solid tumor oncology.