Complex karyotype AML displays G2/M signature and hypersensitivity to PLK1 inhibition.
Blood Adv
; 3(4): 552-563, 2019 02 26.
Article
in En
| MEDLINE
| ID: mdl-30782614
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pteridines
/
Leukemia, Myeloid, Acute
/
Proto-Oncogene Proteins
/
Protein Serine-Threonine Kinases
/
Cell Cycle Proteins
/
Protein Kinase Inhibitors
Limits:
Adult
/
Aged
/
Aged80
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Blood Adv
Year:
2019
Document type:
Article
Affiliation country:
Canada