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<p><i>CBFA2T3::GLIS2</i>-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on <i>JAK2</i> compared to other types of cancer. Using a doxycycline-inducible <i>JAK2</i> knockout (KO) system, we validated <i>JAK2</i> dependency in <i>CBFA2T3::GLIS2</i> cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in <i>CBFA2T3::GLIS2</i>-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in <i>CBFA2T3::GLIS2</i> AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, <i>CBFA2T3::GLIS2</i> AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic <i>NRAS</i> mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a <i>CBFA2T3::GLIS2</i> AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.</p>

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Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月8日

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  • Fanny Gonzales,
  • Constanze Schneider,
  • Gabriela Alexe,
  • Shan Lin,
  • Delan Khalid,
  • Montserrat Alvarez,
  • Allen Basanthakumar,
  • Jana M. Ellegast,
  • Lucy Merickel,
  • Silvi Salhotra,
  • Audrey Taillon,
  • Mariateresa Giaimo,
  • Mark Wunderlich,
  • Marc Ansari,
  • Jennifer A. Perry,
  • Barbara Degar,
  • Yana Pikman,
  • Kimberly Stegmaier

摘要

CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.