Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , Metilación de ADN , Biomarcadores , LeucocitosRESUMEN
The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.
Asunto(s)
Mieloma Múltiple , Animales , Línea Celular Tumoral , Proliferación Celular , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Ratones , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Factores de Transcripción/metabolismoAsunto(s)
Péptidos y Proteínas de Señalización Intracelular , Leucemia , Proteínas de Unión al GTP Monoméricas , Fosfoproteínas , Células Precursoras de Linfocitos T , Animales , GTP Fosfohidrolasas , Haploinsuficiencia/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia/genética , Proteínas de la Membrana , Ratones , Proteínas de Unión al GTP Monoméricas/genética , Mutación , Proteínas Nucleares , Fosfoproteínas/genéticaRESUMEN
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of T-cell ALL. Although genetic mutations hyperactivating cytokine receptor/Ras signaling are prevalent in ETP-ALL, it remains unknown how activated Ras signaling contributes to ETP-ALL. Here, we find that in addition to the frequent oncogenic RAS mutations, wild-type (WT) KRAS transcript level was significantly downregulated in human ETP-ALL cells. Similarly, loss of WT Kras in NrasQ61R/+ mice promoted hyperactivation of extracellular signal-regulated kinase (ERK) signaling, thymocyte hyperproliferation, and expansion of the ETP compartment. Kras-/-; NrasQ61R/+ mice developed early onset of T-cell malignancy that recapitulates many biological and molecular features of human ETP-ALL. Mechanistically, RNA-sequencing analysis and quantitative proteomics study identified that Rasgrp1, a Ras guanine nucleotide exchange factor, was greatly downregulated in mouse and human ETP-ALL. Unexpectedly, hyperactivated Nras/ERK signaling suppressed Rasgrp1 expression and reduced Rasgrp1 level led to increased ERK signaling, thereby establishing a positive feedback loop to augment Nras/ERK signaling and promote cell proliferation. Corroborating our cell line data, Rasgrp1 haploinsufficiency induced Rasgrp1 downregulation and increased phosphorylated ERK level and ETP expansion in NrasQ61R/+ mice. Our study identifies Rasgrp1 as a negative regulator of Ras/ERK signaling in oncogenic Nras-driven ETP-like leukemia.
Asunto(s)
Regulación hacia Abajo , Regulación Leucémica de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido , Proteínas de Unión al GTP Monoméricas , Mutación Missense , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas Proto-Oncogénicas p21(ras)/deficiencia , Sustitución de Aminoácidos , Animales , Proliferación Celular/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition-based therapies for treating advanced/relapsed MM.
