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<p>Activating mutations in <i>STAT6</i> are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; <i>N</i> = 6), and primary human FL WT (<i>N</i> = 11) or mutant (<i>N</i> = 4) for <i>STAT6</i> before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT <i>STAT6</i> we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with <i>STAT6</i> mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing <i>CREBBP</i> mutations and experimentally verified that intact <i>CREBBP</i> is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is <i>RRAGD</i>, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by <i>CREBBP</i> mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.</p>

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STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in follicular lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月5日

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  • Qiangqiang Shao,
  • Karan Bedi,
  • Isabella A. Malek,
  • Kerby Shedden,
  • Sami N. Malek

摘要

Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.