RESUMEN

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

Asunto(s)

Leucemia Mieloide Aguda/metabolismo , Neoplasia Residual/metabolismo , Diferenciación Celular , Humanos , Leucemia Mieloide Aguda/genética , Neoplasia Residual/genética

RESUMEN

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the ß-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/ß-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/ß-catenin interaction.

Asunto(s)

GTP Fosfohidrolasas/metabolismo , Proteínas de la Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factor 1 de Transcripción de Linfocitos T/metabolismo , Transactivadores/metabolismo , beta Catenina/metabolismo , Animales , Trasplante de Médula Ósea , Carcinogénesis/genética , Modelos Animales de Enfermedad , Femenino , GTP Fosfohidrolasas/genética , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Factor 1 de Transcripción de Linfocitos T/genética , Linfocitos T/metabolismo , Transactivadores/genética , Transcriptoma , beta Catenina/genética