RESUMEN

Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations. Initially conducted with a selected library of 5000 small molecules and 20 primary AML specimens, it reveals 5 broad classes of sensitized therapeutic target pathways along with their synergistic patient-specific fingerprints. This novel method opens new avenues for the development of AML personalized therapeutics and may be generalized to other tumor types, for which in vitro cancer stem cell cultures have been developed.

Asunto(s)

Terapia Combinada/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Humanos , Leucemia Mieloide Aguda/patología , Células Tumorales Cultivadas

RESUMEN

Acute myeloid leukemia (AML) is associated with poor clinical outcome and the development of more effective therapies is urgently needed. G protein-coupled receptors (GPCRs) represent attractive therapeutic targets, accounting for approximately 30% of all targets of marketed drugs. Using next-generation sequencing, we studied the expression of 772 GPCRs in 148 genetically diverse AML specimens, normal blood and bone marrow cell populations as well as cord blood-derived CD34-positive cells. Among these receptors, 30 are overexpressed and 19 are downregulated in AML samples compared with normal CD34-positive cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7 and CCRL2), adhesion (CD97, EMR1, EMR2 and GPR114) and purine (including P2RY2 and P2RY13) receptor subfamilies. The downregulated receptors include adhesion GPCRs, such as LPHN1, GPR125, GPR56, CELSR3 and GPR126, protease-activated receptors (F2R and F2RL1) and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, thereby identifying different potential therapeutic targets in these frequent AML subgroups.

Asunto(s)

Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Receptores Acoplados a Proteínas G/genética , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/genética , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Proteínas de Neoplasias/sangre , Transducción de Señal/genética

Asunto(s)

Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-myc/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Humanos , Persona de Mediana Edad , Mutación , Transcriptoma , Translocación Genética , Adulto Joven