CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia


Schmoellerl J., Barbosa I. A. M. , Eder T., Brandstoetter T., Schmidt L., Maurer B., ...Daha Fazla

BLOOD, cilt.136, ss.387-400, 2020 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 136 Konu: 4
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1182/blood.2019003267
  • Dergi Adı: BLOOD
  • Sayfa Sayıları: ss.387-400

Özet

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins de-regulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we de-veloped mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely atten-uated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions. (Blood. 2020;136(4):387-400)