RESUMEN
Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of patients with CNL also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutated leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs, most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we found that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutated CSF3R through the upregulation of Myc-associated gene expression programs.
Asunto(s)
Leucemia Neutrofílica Crónica , Leucemia , Trastornos Mieloproliferativos , Neoplasias , Proteínas Portadoras/genética , Humanos , Leucemia Neutrofílica Crónica/genética , Mutación , Trastornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Receptores del Factor Estimulante de Colonias/genéticaRESUMEN
Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Inhibidores Enzimáticos/administración & dosificación , Histona Demetilasas/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores del Factor Estimulante de Colonias/genética , Factores de Transcripción STAT/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Femenino , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos BALB C , Receptores del Factor Estimulante de Colonias/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Copper-responsive intracellular ATP7B trafficking is crucial for maintaining the copper balance in mammalian hepatocytes and thus copper levels in organs. The copper metabolism domain-containing protein 1 (COMMD1) binds both the ATP7B copper transporter and phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2], whereas COMMD1 loss causes hepatocyte copper accumulation. Although it is clear that COMMD1 is localized to endocytic trafficking complexes, a direct function for COMMD1 in ATP7B trafficking has not yet been defined. In this study, experiments using quantitative colocalization analysis reveal that COMMD1 modulates copper-responsive ATP7B trafficking through recruitment to PtdIns(4,5)P2 Decreased COMMD1 abundance results in loss of ATP7B from lysosomes and the trans-Golgi network (TGN) in high copper conditions, although excess expression of COMMD1 also disrupts ATP7B trafficking and TGN structure. Overexpression of COMMD1 mutated to inhibit PtdIns(4,5)P2 binding has little impact on ATP7B trafficking. A mechanistic PtdIns(4,5)P2-mediated function for COMMD1 is proposed that is consistent with decreased cellular copper export as a result of disruption of the ATP7B trafficking itinerary and early endosome accumulation when COMMD1 is depleted. PtdIns(4,5)P2 interaction with COMMD1 as well as COMMD1 abundance could both be important in maintenance of specific membrane protein trafficking pathways.