HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia.
Oncogene
; 37(20): 2676-2686, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29487418
ABSTRACT
Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling. In vivo targeting of leukemic cell HIF1α inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2α had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1α to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Médula Ósea
/
Leucemia Mieloide Aguda
/
Regulación hacia Arriba
/
Factores Inhibidores de la Migración de Macrófagos
/
Oxidorreductasas Intramoleculares
/
Subunidad alfa del Factor 1 Inducible por Hipoxia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2018
Tipo del documento:
Article
País de afiliación:
Reino Unido