RESUMO
Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.
Assuntos
Neovascularização Fisiológica/efeitos dos fármacos , Proteínas da Gravidez/antagonistas & inibidores , Proteínas da Gravidez/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/prevenção & controle , Corioide/irrigação sanguínea , Modelos Animais de Doenças , Oftalmopatias/patologia , Humanos , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/irrigação sanguínea , Papiloma/induzido quimicamente , Papiloma/prevenção & controle , Fator de Crescimento Placentário , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/prevenção & controleRESUMO
Activating point mutations of the RAS gene act as driver mutations for a subset of precursor-B cell acute lymphoblastic leukaemias (pre-B ALL) and represent an ambitious target for therapeutic approaches. The X box-binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre-B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre-B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL-7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL-7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre-B NRASG12D ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre-B NRASG12D ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRASG12D -mutated pre-B ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Genes ras , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transdução de Sinais , Resposta a Proteínas não Dobradas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genética , Proteína 1 de Ligação a X-Box/genéticaRESUMO
BCR-ABL1-positive acute lymphoblastic leukemia (ALL) cell survival is dependent on the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response. In the current study, we have focused on exploring the efficacy of a simultaneous pharmacological inhibition of BCR-ABL1 and IRE1α in Philadelphia-positive (Ph+) ALL using tyrosine kinase inhibitor (TKI) nilotinib and the IRE1α inhibitor MKC-8866. The combination of 0.5 µM nilotinib and 30 µM MKC-8866 in Ph+ ALL cell lines led to a synergistic effect on cell viability. To mimic this dual inhibition on a genetic level, pre-B-cells from conditional Xbp1+/fl mice were transduced with a BCR-ABL1 construct and with either tamoxifen-inducible cre or empty vector. Cells showed a significant sensitization to the effect of TKIs after the induction of the heterozygous deletion. Finally, we performed a phosphoproteomic analysis on Ph+ ALL cell lines treated with the combination of nilotinib and MKC-8866 to identify potential targets involved in their synergistic effect. An enhanced activation of p38 mitogen-activated protein kinase α (p38α MAPK) was identified. In line with this findings, p38 MAPK and, another important endoplasmic reticulum-stress-related kinase, c-Jun N-terminal kinase (JNK) were found to mediate the potentiated cytotoxic effect induced by the combination of MKC-8866 and nilotinib since the targeting of p38 MAPK with its specific inhibitor BIRB-796 or JNK with JNK-in-8 hindered the synergistic effect observed upon treatment with nilotinib and MKC-8866. In conclusion, the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph+ ALL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Endorribonucleases/antagonistas & inibidores , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Mutações Sintéticas Letais/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/farmacologia , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Sinergismo Farmacológico , Proteínas de Fusão bcr-abl/genética , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos Transgênicos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Proteína 1 de Ligação a X-Box/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The unfolded protein response (UPR) pathway, a stress-induced signaling cascade emanating from the endoplasmic reticulum (ER), regulates the expression and activity of molecules including BiP (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein 1 (XBP1). These molecules are required for terminal differentiation of B cells into plasma cells and expressed at high levels in plasma cell-derived multiple myeloma. Although these molecules have no known role at early stages of B-cell development, here we show that their expression transiently peaks at the pre-B-cell receptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, Prdm1, and Xbp1 consistently induces cellular stress and cell death in normal pre-B cells and in pre-B-cell acute lymphoblastic leukemia (ALL) driven by BCR-ABL1- and NRAS(G12D) oncogenes. Mechanistically, expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. In two clinical trials for children and adults with ALL, high XBP1 mRNA levels at the time of diagnosis predicted poor outcome. A small molecule inhibitor of ERN1-mediated XBP1 activation induced selective cell death of patient-derived pre-B ALL cells in vitro and significantly prolonged survival of transplant recipient mice in vivo. Collectively, these studies reveal that pre-B ALL cells are uniquely vulnerable to ER stress and identify the UPR pathway and its downstream effector XBP1 as novel therapeutic targets to overcome drug resistance in pre-B ALL.
Assuntos
Linfócitos B/fisiologia , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Adulto , Animais , Linfócitos B/metabolismo , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica/farmacologia , Western Blotting , Diferenciação Celular/fisiologia , Criança , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/farmacologia , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/genética , Citometria de Fluxo , Deleção de Genes , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos , Análise em Microsséries , Dados de Sequência Molecular , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição de Fator Regulador X , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/fisiologia , Proteína 1 de Ligação a X-Box , beta-GalactosidaseRESUMO
The RNA-binding protein Musashi-1 has been proposed to maintain stem cell function during development and regenerative processes as a modulator of the Notch-1 signaling pathway. Musashi-1 expression is upregulated in endometrial carcinoma, however, its pathogenetic role in this tumor entity is unknown. Here we investigate the functional impact and mode of action of Musashi-1 on endometrial carcinoma cell behaviour in vitro. Aldehyde dehydrogenase-1 activity and side population (SP) measurement by Hoechst dye exclusion revealed that the Ishikawa endometrial carcinoma cell line contains a pool of putative cancer stem cells. Musashi-1 expression is 20.8-fold upregulated in SP+ compared to SP- and equally distributed between ALDH+ and ALDH- cell pools. siRNA-mediated knockdown of Musashi-1 mRNA expression lead to an altered expression of the signaling receptor Notch-1 and its downstream targets, the transcription factor Hes-1 and the cell cycle regulators p21(WAF1/CIP1) and cyclin B1, as determined by Western blotting and quantitative real-time PCR. Flow cytometric and ELISA analyses revealed that Musashi-1-mediated modulation of these factors exerted an antiproliferative effect on the cell cycle, and increased apoptosis in endometrial carcinoma cells. We conclude that Ishikawa cells contain a subpopulation of cells with stem cell-like properties. Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via the stemness-related factors Notch-1, Hes-1 and p21(WAF1/CIP1) , thus emerging as a novel future target for endometrial carcinoma therapy.
Assuntos
Ciclo Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias do Endométrio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor Notch1/metabolismo , Células-Tronco Adultas/metabolismo , Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Divisão Celular , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas do Tecido Nervoso/genética , RNA Interferente Pequeno , Proteínas de Ligação a RNA/genética , Fatores de Transcrição HES-1RESUMO
The cell surface heparan sulfate proteoglycan syndecan-1 (CD138) modulates the activity of chemokines, cytokines, integrins, and other adhesion molecules which play important roles in the regulation of inflammation. We have previously shown that syndecan-1-deficient murine leukocytes display increased interactions with endothelial cells and increased diapedesis in vivo and in vitro. In this study, we demonstrate that syndecan-1 has an important function as a negative modulator in the murine contact allergy model of oxazolone-mediated delayed-type hypersensitivity (DTH). Following elicitation of the DTH response, syndecan-1-deficient mice showed an increase in leukocyte recruitment, resulting in an increased and prolonged edema formation. Expression of the cytokines TNF-alpha and IL-6 of the chemokines CCL5/RANTES and CCL-3/MIP-1alpha and of the adhesion molecule ICAM-1 were significantly increased in syndecan-1-deficient compared with wild-type mice. In wild-type mice, syndecan-1 mRNA and protein expression was reduced during the DTH response. The differentially increased adhesion of syndecan-1-deficient leukocytes to ICAM-1 was efficiently inhibited in vitro by CD18-blocking Abs, which emerges as one mechanistic explanation for the anti-inflammatory effects of syndecan-1. Collectively, our results show an important role of syndecan-1 in the contact DTH reaction, identifying syndecan-1 as a novel target in anti-inflammatory therapy.
Assuntos
Hipersensibilidade Tardia/imunologia , Sindecana-1/imunologia , Animais , Movimento Celular/imunologia , Epitopos/imunologia , Heparitina Sulfato/imunologia , Hipersensibilidade Tardia/genética , Hipersensibilidade Tardia/metabolismo , Hipersensibilidade Tardia/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos/citologia , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regulação para CimaRESUMO
The intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response (UPR) from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis. Cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, depend on an efficiently operating UPR to maintain proteostasis. Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy. For mast cell leukemia (MCL) the efficacy of both approaches, by utilizing the KITV560G,D816V-positive MCL cell line HMC-1.2, was investigated. We show that HMC-1.2 cells display a tonic activation of the IRE1α arm of the UPR, which constitutively generates spliced XBP1. Inhibition of IRE1α by different types of inhibitors (MKC-8866, STF-083010, and KIRA6) suppressed proliferation at concentrations needed for blockade of IRE1α-mediated XBP1 splicing. At higher concentrations, these inhibitors triggered an apoptotic response. Blocking the proteasome by bortezomib, which confers an exaggerated UPR, resulted in a marked cytotoxic response. Bortezomib treatment also caused activation of the kinase JNK, which played a pro-proliferative and anti-apoptotic role. Hence, the combination of bortezomib with a JNK inhibitor synergized to induce cell death. In summary, the UPR can be addressed as an effective therapeutic target against KITD816V-positive MCL.
RESUMO
The VEGF family of pro-angiogenic factors has represented a pillar for targeted cancer therapy for more than a decade. In comparison, the field of protein homeostasis (proteostasis) focusing on the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, has just recently emerged as an attractive anti-cancer approach. Recent findings suggest that both signaling pathways are incontestably interrelated to ensure cell survival. Herein, we summarize recent findings that demonstrate how these two fundamental aspects of cancer cell survival intersect and provide genetic and pharmacological evidence of the interplay between angiogenic factors such as VEGF-A or PlGF and the individual members of the UPR such as IRE1, PERK and ATF6. We further describe how this interaction does not only affect the cancer cells, but also the surrounding microenvironmental niche that is also involved in tumor progression. Furthermore, by summarizing the recent therapeutic implications of both anti-angiogenic and proteostatic approaches, we emphasize how these novel findings could be used synergistically to improve cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/patologia , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Risk stratification based on cytogenetics of acute myeloid leukemia (AML) remains imprecise. The introduction of novel genetic and epigenetic markers has helped to close this gap and increased the specificity of risk stratification, although most studies have been conducted in specific AML subpopulations. In order to overcome this limitation, we used a genome-wide approach in multiple AML populations to develop a robust prediction model for AML survival. METHODS: We conducted a genome-wide expression analysis of two data sets from AML patients enrolled into the AMLCG-1999 trial and from the Tumor Cancer Genome Atlas (TCGA) to develop a prognostic score to refine current risk classification and performed a validation on two data sets of the National Taiwan University Hospital (NTUH) and an independent AMLCG cohort. RESULTS: In our training set, using a stringent multi-step approach, we identified a small three-gene prognostic scoring system, named Tri-AML score (TriAS) which highly correlated with overall survival (OS). Multivariate analysis revealed TriAS to be an independent prognostic factor in all tested training and additional validation sets, even including age, current cytogenetic-based risk stratification, and three other recently developed expression-based scoring models for AML. CONCLUSIONS: The Tri-AML score allows robust and clinically practical risk stratification for the outcome of AML patients. TriAS substantially refined current ELN risk stratification assigning 44.5 % of the patients into a different risk category.
Assuntos
Leucemia Mieloide Aguda/genética , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Citogenética , Feminino , Genômica , Humanos , Armazenamento e Recuperação da Informação/métodos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Masculino , Prognóstico , Aprendizado de Máquina Supervisionado , Taxa de SobrevidaRESUMO
Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1α RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1α inhibition induced caspase-dependent apoptosis and G1 cell cycle arrest at least partially by regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and cyclin D1), as well as chaperone proteins. Xbp1 deleted murine bone marrow cells were resistant to growth inhibition by IRE1α inhibitors. Combination of HNA with either bortezomib or AS2O3 was synergistic in AML cytotoxicity associated with induction of p-JNK and reduction of p-PI3K and p-MAPK. Inhibition of IRE1α RNase activity increased expression of many miRs in AML cells including miR-34a. Inhibition of miR-34a conferred cellular resistance to HNA. Our results strongly suggest that targeting IRE1α driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML.
Assuntos
Endorribonucleases/metabolismo , Leucemia Mieloide Aguda/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Endorribonucleases/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleases/antagonistas & inibidores , Ribonucleases/metabolismo , Transdução de Sinais , Transfecção , Resposta a Proteínas não Dobradas , Regulação para Cima , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
BACKGROUND: Proteostasis is defined by the orchestrated control of anabolic and catabolic protein pathways. Disruption of proteostasis results in cell stress and adaptation to proteostasis imbalance is mediated by adaptive pathways such as the Heat Shock Response (including heat-shock proteins) or the unfolded protein response (UPR). The BCR-ABL1 kinase (Philadelphia chromosome) is the hallmark of chronic myeloid leukemia (CML) and defines a historically poor subset in acute lymphoblastic leukemia (Ph(+) ALL). We previously demonstrated the importance of the UPR and particularly of the IRE1/XBP1 signaling axis in Ph(+) ALL, while others demonstrated the therapeutic relevance of HSP70 in ALL. In this regard, HSP70 is regulated by smaller HSP40 s, whose function is so far poorly characterized. RESULTS: Herein, we characterize the expression of HSP40 s in Ph(+) ALL and CML. We show that these genes are not regulated in a pan-class manner and identify a homologous gene pair, namely Auxilin-1 (DNAJC6) and Auxilin-2 (GAK) with a unique expression profile. Overexpression of Auxilin-2, the ubiquitously expressed homologue of Auxilin-1 correlated with superior clinical outcome in ALL and was tightly linked to both IRE1 RNase and BCR-ABL1 kinase activities. CONCLUSIONS: Our findings suggest that HSP40 gens are uniquely regulated and provide a rationale for further studies between BCR-ABL1/IRE1-based therapies in combination with HSP40 inhibitors, thus opening potentially novel therapeutic avenues.
RESUMO
The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.
Assuntos
Leucemia/genética , Resposta a Proteínas não Dobradas/genética , Sobrevivência Celular , Humanos , Transdução de SinaisRESUMO
The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.
Assuntos
Leucemia Mieloide Aguda/genética , Proteínas dos Microfilamentos/genética , Proteínas de Neoplasias/genética , Linhagem Celular Tumoral , Aberrações Cromossômicas , Análise por Conglomerados , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Cariótipo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Proteínas dos Microfilamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteína 1 Parceira de Translocação de RUNX1 , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Imatinib has revolutionized the treatment of Bcr-Abl1(+) chronic myeloid leukemia (CML), but, in most patients, some leukemia cells persist despite continued therapy, while others become resistant. Here, we report that PlGF levels are elevated in CML and that PlGF produced by bone marrow stromal cells (BMSCs) aggravates disease severity. CML cells foster a soil for their own growth by inducing BMSCs to upregulate PlGF, which not only stimulates BM angiogenesis, but also promotes CML proliferation and metabolism, in part independently of Bcr-Abl1 signaling. Anti-PlGF treatment prolongs survival of imatinib-sensitive and -resistant CML mice and adds to the anti-CML activity of imatinib. These results may warrant further investigation of the therapeutic potential of PlGF inhibition for (imatinib-resistant) CML.