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1.
Blood ; 143(20): 2059-2072, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38437498

RESUMEN

ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.


Asunto(s)
ADN Helicasas , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Proteínas Nucleares , Nucleofosmina , Proteínas Proto-Oncogénicas , Factores de Transcripción , Humanos , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Ratones , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/genética , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Proteínas que Contienen Bromodominio , Proteínas
2.
Blood Cancer J ; 14(1): 25, 2024 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-38316746

RESUMEN

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Homoharringtonina , Plaquetas/patología , Trastornos de las Plaquetas Sanguíneas/complicaciones , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/patología , Proteínas Proto-Oncogénicas c-bcl-2
3.
Leukemia ; 38(3): 545-556, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38086946

RESUMEN

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear ß-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-ß signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína del Locus del Complejo MDS1 y EV11/genética , Proteína del Locus del Complejo MDS1 y EV11/metabolismo , Proteínas Nucleares/genética , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Epigénesis Genética , Proto-Oncogenes , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular/genética
4.
Blood Cancer J ; 13(1): 53, 2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-37055414

RESUMEN

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.


Asunto(s)
Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Humanos , Proteínas de Ciclo Celular/genética , Epigénesis Genética , Histona Demetilasas/genética , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Recurrencia Local de Neoplasia/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/genética
5.
Leukemia ; 37(6): 1336-1348, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36977823

RESUMEN

In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Anciano , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Panobinostat , Recurrencia Local de Neoplasia , Mutación , Citarabina/farmacología , Citarabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéutico
8.
Pharmacol Rev ; 74(1): 18-47, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34987087

RESUMEN

ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.


Asunto(s)
Neoplasias , Receptor ErbB-4 , Transducción de Señal , Humanos , Neoplasias/genética , Receptor ErbB-4/genética
9.
Blood Cancer J ; 12(1): 5, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-35017466

RESUMEN

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.


Asunto(s)
Antineoplásicos/farmacología , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteína de la Leucemia Mieloide-Linfoide/genética , Nucleofosmina/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Aminopiridinas/farmacología , Bencimidazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Reordenamiento Génico/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas/genética , Sulfonamidas/farmacología
10.
Blood ; 139(6): 907-921, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-34601571

RESUMEN

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.


Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Homoharringtonina/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Sulfonamidas/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/genética , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores
11.
Blood Cancer J ; 11(5): 98, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-34016956

RESUMEN

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Unión al ADN/antagonistas & inhibidores , Histona Demetilasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Silenciador del Gen/efectos de los fármacos , Histona Demetilasas/genética , Humanos , Leucemia Mieloide Aguda/genética , Terapia Molecular Dirigida , Trastornos Mieloproliferativos/genética , Factores de Transcripción/genética , Transcriptoma/efectos de los fármacos
12.
Blood Cancer J ; 11(3): 64, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753715

RESUMEN

Ecotropic viral integration site 1 (Evi1) was discovered in 1988 as a common site of ecotropic viral integration resulting in myeloid malignancies in mice. EVI1 is an oncogenic zinc-finger transcription factor whose overexpression contributes to disease progression and an aggressive phenotype, correlating with poor clinical outcome in myeloid malignancies. Despite progress in understanding the biology of EVI1 dysregulation, significant improvements in therapeutic outcome remain elusive. Here, we highlight advances in understanding EVI1 biology and discuss how this new knowledge informs development of novel therapeutic interventions. EVI1 is overexpression is correlated with poor outcome in some epithelial cancers. However, the focus of this review is the genetic lesions, biology, and current therapeutics of myeloid malignancies overexpressing EVI1.


Asunto(s)
Leucemia Mieloide/genética , Proteína del Locus del Complejo MDS1 y EV11/genética , Animales , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Leucemia Mieloide/patología , Leucemia Mieloide/terapia , Mutación , Procesamiento Proteico-Postraduccional , Activación Transcripcional
13.
Leukemia ; 35(9): 2621-2634, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33654205

RESUMEN

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas/metabolismo , Proteolisis , Adenina/administración & dosificación , Adenina/análogos & derivados , Animales , Apoptosis , Biomarcadores de Tumor/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Piperidinas/administración & dosificación , Proteínas/genética , Sulfonamidas/administración & dosificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
14.
PLoS One ; 15(12): e0243901, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33378376

RESUMEN

Whereas recent clinical studies report metastatic melanoma survival rates high as 30-50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2ß) functions as a partial agonist at ErbB4. NRG2ß/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z' > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.


Asunto(s)
Proliferación Celular/genética , Melanoma/genética , Factores de Crecimiento Nervioso/genética , Receptor ErbB-4/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Mutación con Ganancia de Función/genética , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Fosforilación/genética , Receptor ErbB-4/agonistas , Receptor ErbB-4/antagonistas & inhibidores , Transducción de Señal/genética , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
15.
Blood ; 135(15): 1255-1269, 2020 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-32068780

RESUMEN

The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Factores de Transcripción/metabolismo , beta Catenina/metabolismo
16.
Blood ; 134(1): 59-73, 2019 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-31023702

RESUMEN

RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expression-mimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents for AML expressing somatic or germline mtRUNX1.


Asunto(s)
Antineoplásicos/farmacología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Técnicas de Silenciamiento del Gen , Mutación de Línea Germinal , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Ratones
17.
Blood Cancer J ; 9(2): 4, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30647404

RESUMEN

First-generation bromodomain extra-terminal protein (BETP) inhibitors (BETi) (e.g., OTX015) that disrupt binding of BETP BRD4 to chromatin transcriptionally attenuate AML-relevant progrowth and prosurvival oncoproteins. BETi treatment induces apoptosis of AML BPCs, reduces in vivo AML burden and induces clinical remissions in a minority of AML patients. Clinical efficacy of more potent BETis, e.g., ABBV-075 (AbbVie, Inc.), is being evaluated. Venetoclax and A-1210477 bind and inhibit the antiapoptotic activity of BCL2 and MCL1, respectively, lowering the threshold for apoptosis. BETi treatment is shown here to perturb accessible chromatin and activity of enhancers/promoters, attenuating MYC, CDK6, MCL1 and BCL2, while inducing BIM, HEXIM1, CDKN1A expressions and apoptosis of AML cells. Treatment with venetoclax increased MCL1 protein levels, but cotreatment with ABBV-075 reduced MCL1 and Bcl-xL levels. ABBV-075 cotreatment synergistically induced apoptosis with venetoclax or A-1210477 in patient-derived, CD34+ AML cells. Compared to treatment with either agent alone, cotreatment with ABBV-075 and venetoclax was significantly more effective in reducing AML cell-burden and improving survival, without inducing toxicity, in AML-engrafted immune-depleted mice. These findings highlight the basis of superior activity and support interrogation of clinical efficacy and safety of cotreatment with BETi and BCL2 or MCL1 inhibitor in AML.


Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Sitios de Unión , Biomarcadores de Tumor , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Indoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Unión Proteica , Piridonas/farmacología , Sulfonamidas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Leukemia ; 33(6): 1373-1386, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30575820

RESUMEN

Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear ß-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of ß-catenin or treatment with BC2059 that disrupts binding of ß-catenin to TBL1X (TBL1) depleted nuclear ß-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of ß-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of ß-catenin and BETP antagonists against post-MPN sAML BPCs.


Asunto(s)
Núcleo Celular/efectos de los fármacos , Sinergismo Farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , beta Catenina/antagonistas & inhibidores , Acetanilidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Sistemas CRISPR-Cas , Núcleo Celular/metabolismo , Núcleo Celular/patología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Nitrilos , Pirazoles/farmacología , Pirimidinas , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/genética , beta Catenina/metabolismo
19.
Mol Cell ; 69(5): 729-743.e7, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29499131

RESUMEN

MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid ß-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.


Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Metabolismo de los Lípidos/fisiología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Ácido Palmítico/metabolismo , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Animales , Línea Celular , Ratones , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Oxidación-Reducción , Estructura Secundaria de Proteína
20.
Leukemia ; 31(3): 678-687, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27677740

RESUMEN

Myeloproliferative neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that responds to treatment with the JAK1 and 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary acute myeloid leukemia (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extraterminal) protein inhibitor (BETi), for example, JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells. Reverse-phase protein array, mass-cytometry and Western analyses revealed that BETi treatment attenuated the protein expressions of c-MYC, p-STAT5, Bcl-xL, CDK4/6, PIM1 and IL-7R, whereas it concomitantly induced the levels of HEXIM1, p21 and BIM in the sAML cells. Co-treatment with BETi and ruxolitinib synergistically induced apoptosis of cultured and PD sAML cells, as well as significantly improved survival of immune-depleted mice engrafted with human sAML cells. Although BETi or heat shock protein 90 inhibitor (HSP90i) alone exerted lethal activity, cotreatment with BETi and HSP90i was synergistically lethal against the ruxolitinib-persister or ruxolitinib-resistant sAML cells. Collectively, these findings further support in vivo testing of BETi-based combinations with JAKi and HSP90i against post-MPN sAML cells.


Asunto(s)
Antineoplásicos/farmacología , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Trastornos Mieloproliferativos/complicaciones , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Unión al ARN/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Biomarcadores , Caspasas/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Genes myc , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Ratones , Dominios y Motivos de Interacción de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Receptores de Interleucina-7/metabolismo , Factor de Transcripción STAT5/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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