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1.
Blood Adv ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38996202

RESUMEN

Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may impact leukemia is less well studied. Using annexin A5 (ANXA 5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) versus chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor (TNF)α dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases -catenin and hypoxia-inducible factor (HIF) 1 α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML compared to other hematological malignancies. Further, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 (COX2)), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared to cytarabine alone. Taken together, TNFα/ANXA5/NF-kB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and AML patients with 'inflammatory AML' may benefit from antiphlogistic agents as adjunct therapy.

2.
Leukemia ; 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965370

RESUMEN

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.

3.
Blood ; 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38691678

RESUMEN

Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.

4.
Cell Rep Med ; 5(5): 101565, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38776875

RESUMEN

CML is readily treatable with tyrosine kinase inhibitors (TKIs); however, resistance occurs, with the disease curable in only ∼15%-20% of patients. Using integrated functional genomics, Adnan Awad et al.1 identify agents effective against CML stem cells and describe mechanisms underlying TKI resistance.


Asunto(s)
Resistencia a Antineoplásicos , Genómica , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Genómica/métodos
6.
Cell Genom ; 3(12): 100426, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38116120

RESUMEN

Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.

7.
Mol Oncol ; 17(12): 2493-2506, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37872885

RESUMEN

Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in myeloid neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter- and intra-patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analyses of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs.


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Epigénesis Genética , Mutación , Células Madre , Células Madre Neoplásicas/patología
8.
Nat Commun ; 14(1): 6242, 2023 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-37802982

RESUMEN

Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, ß-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.


Asunto(s)
Leucemia Mieloide Aguda , Receptores Sensibles al Calcio , Humanos , Receptores Sensibles al Calcio/genética , Proteínas Proto-Oncogénicas c-myc , Calcio , Proteínas de Fusión Oncogénica/metabolismo , Transducción de Señal , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Citarabina , Microambiente Tumoral
9.
Nat Genet ; 55(9): 1542-1554, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37580596

RESUMEN

Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.


Asunto(s)
Cromatina , Leucemia , Humanos , Cromatina/genética , Linaje de la Célula/genética , Hematopoyesis/genética , Diferenciación Celular/genética , Factores de Transcripción/genética
10.
Nat Commun ; 14(1): 2132, 2023 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-37059720

RESUMEN

Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.


Asunto(s)
Leucemia Mieloide Aguda , Manosa , Humanos , Muerte Celular , Citarabina/farmacología , Línea Celular Tumoral , Leucemia Mieloide Aguda/metabolismo , Apoptosis , Tirosina Quinasa 3 Similar a fms
11.
Clin Cancer Res ; 29(4): 711-722, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36350312

RESUMEN

PURPOSE: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). PATIENTS AND METHODS: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively. CONCLUSIONS: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.


Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Linfoma no Hodgkin , Trombocitopenia , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Neoplasias Hematológicas/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico
12.
Blood ; 141(14): 1737-1754, 2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-36577137

RESUMEN

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas de Unión a la Región de Fijación a la Matriz , Humanos , Proteómica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Transcripción/genética , Proteínas Asociadas a Matriz Nuclear , Cromatina , Receptores de Estrógenos/genética , Receptores de Estrógenos/uso terapéutico , Proteínas de Unión a la Región de Fijación a la Matriz/genética
13.
iScience ; 25(12): 105622, 2022 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-36465109

RESUMEN

Several studies have documented aberrant RNA editing patterns across multiple tumors across large patient cohorts from The Cancer Genome Atlas (TCGA). However, studies on understanding the role of RNA editing in acute myeloid leukemia (AML) have been limited to smaller sample sizes. Using high throughput transcriptomic data from the TCGA, we demonstrated higher levels of editing as a predictor of poor outcome within the AML patient samples. Moreover, differential editing patterns were observed across individual AML genotypes. We also could demonstrate a negative association between the degree of editing and mRNA abundance for some transcripts, identifying the potential regulatory potential of RNA-editing in altering gene expression in AML. Further edQTL analysis suggests potential cis-regulatory mechanisms in RNA editing variation. Our work suggests a functional and regulatory role of RNA editing in the pathogenesis of AML and we extended our analysis to gain insight into the factors influencing altered levels of editing.

14.
STAR Protoc ; 3(4): 101770, 2022 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-36242770

RESUMEN

Recurrent gene mutations often cooperate in a predefined stepwise and synergistic manner to alter global transcription, through directly or indirectly remodeling epigenetic landscape on linear and three-dimensional (3D) scales. Here, we present a multiomics data integration approach to investigate the impact of gene mutational synergy on transcription, chromatin states, and 3D chromatin organization in a murine leukemia model. This protocol provides an executable framework to study epigenetic remodeling induced by cooperating gene mutations and to identify the critical regulatory network involved. For complete details on the use and execution of this protocol, please refer to Yun et al. (2021).


Asunto(s)
Ensamble y Desensamble de Cromatina , Multiómica , Animales , Ratones , Cromatina , Mutación
15.
Sci Adv ; 8(31): eabn4886, 2022 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-35921412

RESUMEN

Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.


Asunto(s)
Leucemia , Preleucemia , Animales , Diferenciación Celular , Leucemia/genética , Ratones , Preleucemia/genética , Preleucemia/patología , Biosíntesis de Proteínas
16.
Nat Commun ; 13(1): 4622, 2022 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-35941135

RESUMEN

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Análisis Citogenético , Citometría de Flujo/métodos , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual
18.
Leukemia ; 36(6): 1585-1595, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35474100

RESUMEN

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.


Asunto(s)
Cistina , Leucemia Mieloide Aguda , Línea Celular Tumoral , Cisteína , Cistina/metabolismo , Cistina/uso terapéutico , Daunorrubicina/farmacología , Daunorrubicina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Nucleares , Sulfasalazina/farmacología , Sulfasalazina/uso terapéutico
19.
Sci Signal ; 15(730): eabo0059, 2022 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-35439022

RESUMEN

Mutations in multiple cancers may synergize to alter the cellular epigenetic and transcriptional state and corrupt key signaling pathways. In this issue of Science Signaling, Pedicona et al. illustrate how the two processes intersect to regulate cellular differentiation in acute myeloid leukemia (AML) and show how inhibition of epigenetic regulators promotes sensitivity to kinase inhibitors.


Asunto(s)
Leucemia Mieloide Aguda , Epigénesis Genética , Epigenómica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación , Transducción de Señal/genética
20.
Blood ; 139(16): 2471-2482, 2022 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-35134130

RESUMEN

The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins of a primary cancer. We used a novel approach to prioritize immunotherapy targets and identified a cell surface protein not previously implicated in myeloma, semaphorin-4A (SEMA4A). Using knock-down by short-hairpin RNA and CRISPR/nuclease-dead Cas9 (dCas9), we show that expression of SEMA4A is essential for normal myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate the protein to avoid detection. We further show that SEMA4A would not be identified as a myeloma therapeutic target by standard CRISPR/Cas9 knockout screens because of exon skipping. Finally, we potently and selectively targeted SEMA4A with a novel antibody-drug conjugate in vitro and in vivo.


Asunto(s)
Mieloma Múltiple , Semaforinas , Membrana Celular/metabolismo , Humanos , Factores Inmunológicos , Inmunoterapia , Proteínas de la Membrana , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Proteómica , Semaforinas/genética , Semaforinas/metabolismo
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