Scholarlink

<p>Myeloid leukaemias harboring complex karyotypes present several unrelated cytogenetic abnormalities and form a distinct subset of AML linked to a dismal prognosis. Currently, no effective options are available for the treatment of those patients, and the discovery of novel therapeutic strategies represent an urgent clinical priority. We previously developed a bioinformatic framework for the identification of novel molecular vulnerabilities for disease stratification and treatment and observed SPINK2, a serine protease inhibitor Kazal-type 2, as a novel and promising candidate target in AML, with particularly pronounced effects in complex karyotype patients. Using publicly available bulk and single cell RNA-seq datasets, we discovered a robust association between <i>SPINK2</i> and cell cycle regulators, most notably S-phase genes. By performing shRNA-mediated genetic manipulation of <i>SPINK2</i> expression in a complex karyotype AML cell lines, we observed a profound impairment of proliferation coupled with an induction of terminal myeloid commitment. Moreover, <i>SPINK2</i>-deficient FUJIOKA cells revealed a significant association between <i>SPINK2</i> and <i>MECOM</i> expression, consistent with findings in patients harbouring complex karyotypes, yet absent in other AML subsets from the TARGET-AML cohort. Our findings suggest a novel potential correlation between <i>SPINK2</i> and <i>MECOM</i> expression in complex karyotype leukemias and warrant further investigation into the underlying molecular mechanisms through which the SPINK2-MECOM axis enforces aberrant self-renewal and the development of novel targeted approaches aimed at modulating its expression in complex karyotypic AML.</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

SPINK2 silencing suppresses leukemic proliferation and restores myeloid commitment via MECOM downregulation in acute myeloid leukaemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月3日

查看全文
  • Antonio Benedetto Ventura,
  • Tiziana Loconte,
  • Amer Ahmed,
  • Lucia Deligio,
  • Antonio Negri,
  • Gabriella D’Angelo,
  • Daria Di Molfetta,
  • Pierre Cauchy,
  • Barbara Mandriani,
  • Xiao Zhang,
  • Crescenza Pasciolla,
  • Antonello Rana,
  • Angela Iacobazzi,
  • Giacomo Loseto,
  • Mauro Cives,
  • Luigi Viggiano,
  • Francesco Massimo Lasorsa,
  • Attilio Guarini,
  • Maria Carmela Vegliante,
  • Sabino Ciavarella,
  • Giancarlo Castellano,
  • Giuseppe Fiermonte,
  • Giacomo Volpe

摘要

Myeloid leukaemias harboring complex karyotypes present several unrelated cytogenetic abnormalities and form a distinct subset of AML linked to a dismal prognosis. Currently, no effective options are available for the treatment of those patients, and the discovery of novel therapeutic strategies represent an urgent clinical priority. We previously developed a bioinformatic framework for the identification of novel molecular vulnerabilities for disease stratification and treatment and observed SPINK2, a serine protease inhibitor Kazal-type 2, as a novel and promising candidate target in AML, with particularly pronounced effects in complex karyotype patients. Using publicly available bulk and single cell RNA-seq datasets, we discovered a robust association between SPINK2 and cell cycle regulators, most notably S-phase genes. By performing shRNA-mediated genetic manipulation of SPINK2 expression in a complex karyotype AML cell lines, we observed a profound impairment of proliferation coupled with an induction of terminal myeloid commitment. Moreover, SPINK2-deficient FUJIOKA cells revealed a significant association between SPINK2 and MECOM expression, consistent with findings in patients harbouring complex karyotypes, yet absent in other AML subsets from the TARGET-AML cohort. Our findings suggest a novel potential correlation between SPINK2 and MECOM expression in complex karyotype leukemias and warrant further investigation into the underlying molecular mechanisms through which the SPINK2-MECOM axis enforces aberrant self-renewal and the development of novel targeted approaches aimed at modulating its expression in complex karyotypic AML.