Scholarlink

<p>Children with Down syndrome (DS) frequently develop transient abnormal myelopoiesis that can evolve to the myeloid leukemia of DS (ML-DS). TAM spontaneously resolves in most cases but progresses to ML-DS with additional mutations, most commonly in the cohesin complex. However, the mechanisms by which these alterations promote leukemia are unknown. We leveraged the <i>RAD21</i>-mutant CMY cell line and <i>RAD21</i>-corrected CMY isogenic clones, as well as patient data, to investigate the effect of cohesin mutations during leukemia progression. RNA-sequencing revealed that HLA-class II genes were significantly down-regulated with cohesin mutations. Furthermore, HLA-DR was found to be lower in ML-DS relative to TAM, and these decreased levels were associated with increased risk of leukemia progression. Multi-omic analyses revealed that haploinsufficiency of <i>RAD21</i> altered chromatin accessibility and impaired the occupancy of GATA1s and CIITA, the master regulator of HLA-class II gene expression. Chromatin binding of CIITA was increased with <i>RAD21</i> correction, providing a mechanism by which restoration of cohesin improves HLA-class II expression. Finally, decreased levels of <i>RAD21</i> or <i>STAG2</i> expression in other subtypes of AML also exhibited reduced expression of HLA-class II genes. Thus, cohesin may contribute to leukemia by altering HLA-class II gene expression.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The effect of cohesin mutations on HLA-class II expression in the myeloid leukemia of Down syndrome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

查看全文
  • Austin C. Boucher,
  • Wojciech Rosikiewicz,
  • Anitria Cotton,
  • Amber L. Broadhurst,
  • Te Ling,
  • Rishika Vadlamudi,
  • Melanie Bremm,
  • Anna-Lena Schmell,
  • Lahiri Konada,
  • Madeline Niederkorn,
  • Josiah D. Murray,
  • Yichao Li,
  • Shilpa Narina,
  • Sarah Inglott,
  • Anindita Roy,
  • Philip Ancliff,
  • Ricky Tirtakusuma,
  • Jing Ma,
  • Michael P. Walsh,
  • Jeffery M. Klco,
  • Paul G. Thomas,
  • Yiwen Wang,
  • Aristotelis Tsirigos,
  • Yong Cheng,
  • Beisi Xu,
  • Xiaotu Ma,
  • Soheil Meshinchi,
  • Elvin Wagenblast,
  • Shondra M. Pruett-Miller,
  • Sridhar Rao,
  • Gang Wu,
  • Yunusa Olufadi,
  • Guolian Kang,
  • Zuzana Tothova,
  • Jeffrey W. Taub,
  • Yubin Ge,
  • Paresh Vyas,
  • Jan-Henning Klusmann,
  • John D. Crispino

摘要

Children with Down syndrome (DS) frequently develop transient abnormal myelopoiesis that can evolve to the myeloid leukemia of DS (ML-DS). TAM spontaneously resolves in most cases but progresses to ML-DS with additional mutations, most commonly in the cohesin complex. However, the mechanisms by which these alterations promote leukemia are unknown. We leveraged the RAD21-mutant CMY cell line and RAD21-corrected CMY isogenic clones, as well as patient data, to investigate the effect of cohesin mutations during leukemia progression. RNA-sequencing revealed that HLA-class II genes were significantly down-regulated with cohesin mutations. Furthermore, HLA-DR was found to be lower in ML-DS relative to TAM, and these decreased levels were associated with increased risk of leukemia progression. Multi-omic analyses revealed that haploinsufficiency of RAD21 altered chromatin accessibility and impaired the occupancy of GATA1s and CIITA, the master regulator of HLA-class II gene expression. Chromatin binding of CIITA was increased with RAD21 correction, providing a mechanism by which restoration of cohesin improves HLA-class II expression. Finally, decreased levels of RAD21 or STAG2 expression in other subtypes of AML also exhibited reduced expression of HLA-class II genes. Thus, cohesin may contribute to leukemia by altering HLA-class II gene expression.