Complex karyotype AML displays G2/M signature and hypersensitivity to PLK1 inhibition

Blood Adv. 2019 Feb 26;3(4):552-563. doi: 10.1182/bloodadvances.2018028480.

Abstract

Patients diagnosed with acute myeloid leukemia with complex karyotype (CK AML) have an adverse prognosis using current therapies, especially when accompanied by TP53 alterations. We hereby report the RNA-sequencing analysis of the 68 CK AML samples included in the Leucegene 415 patient cohort. We confirm the frequent occurrence of TP53 alterations in this subgroup and further characterize the allele expression profile and transcript alterations of this gene. We also document that the RAS pathway (N/KRAS, NF1, PTPN11, BRAF) is frequently altered in this disease. Targeted chemical interrogation of genetically characterized primary CK AML samples identifies polo-like kinase 1 (PLK1) inhibitors as the most selective agents for this disease subgroup. TP53 status did not alter sensitivity to PLK1 inhibitors. Interestingly, CK AML specimens display a G2/M transcriptomic signature that includes higher expression levels of PLK1 and correlates with PLK1 inhibition sensitivity. Together, our results highlight vulnerability in CK AML. In line with these in vitro data, volasertib shows a strong anti-AML activity in xenotransplantation mouse models of human adverse AML. Considering that PLK1 inhibitors are currently being investigated clinically in AML and myelodysplastic syndromes, our results provide a new rationale for PLK1-directed therapy in patients with adverse cytogenetic AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Karyotype
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • M Phase Cell Cycle Checkpoints / drug effects
  • Male
  • Mice
  • Middle Aged
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Pteridines / therapeutic use*
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult

Substances

  • BI 6727
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pteridines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1