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2.
Blood ; 141(13): 1610-1625, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36508699

RESUMO

Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.


Assuntos
Leucemia Megacarioblástica Aguda , Leucemia Mieloide Aguda , Linfoma de Células B , Animais , Camundongos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteína bcl-X/genética , Leucemia Megacarioblástica Aguda/tratamento farmacológico , Leucemia Megacarioblástica Aguda/genética , Diferenciação Celular , Apoptose
3.
Genes Dev ; 29(18): 1915-29, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26385962

RESUMO

The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.


Assuntos
Diferenciação Celular/genética , Células-Tronco Hematopoéticas/citologia , Proteínas Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células da Medula Óssea/fisiologia , Adesão Celular/genética , Movimento Celular/genética , Transformação Celular Neoplásica/genética , Células Cultivadas , Deleção de Genes , Camundongos , Proteínas Oncogênicas/genética , Fatores de Transcrição/genética , Regulador Transcricional ERG
4.
Br J Haematol ; 199(4): 539-548, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36083781

RESUMO

Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)-based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy-related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30- and 90-day mortality between DR and non-DR patients. Furthermore, DR did not affect median relapse-free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0-41.7) months; non-DR, 15.0 (12.3-19.3)] with an adjusted difference in five-year restricted mean survival time (Δ5y-RMST) of 0.2 (-8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non-DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y-RMST of 0.8 (-5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject.


Assuntos
Leucemia Mieloide Aguda , Sobrepeso , Adulto , Humanos , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Estudos de Coortes , Redução da Medicação , Recidiva Local de Neoplasia/tratamento farmacológico , Indução de Remissão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dinamarca/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
5.
Br J Haematol ; 193(3): 482-487, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33222154

RESUMO

In the present study, we quantify the progress in overall survival (OS) during the period 2000-2016 among Danish patients with acute myeloid leukaemia (AML). This population-based study, including 3820 adult patients with AML, demonstrates a significantly improved OS over time with the 2-year age-standardised OS increasing from 22% in 2002 to 31% in 2016. The improvement in OS was exclusively seen in patients with AML aged ≥50 years, with absolute improvements in 2-year OS from 2002 to 2016 of ≥10% among patients aged 50-75 years and a small absolute increase in those aged >75 years.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Dinamarca/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
6.
Br J Haematol ; 190(2): 236-243, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32316076

RESUMO

With rising life expectancy, the importance of patient-related prognostic factors and how to integrate such data into clinical decision-making becomes increasingly important. The aim of this study was to evaluate the prognostic impact of smoking status in patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy. We conducted a nationwide cohort study based on data obtained from the Danish National Leukaemia Registry (DNLR). The study comprised Danish patients aged 18-75 years, diagnosed with AML between 1 January 2000 and 31 December 2012. Medical records were reviewed and data on smoking status were collected. A total of 1040 patients (median age 59 years) were included, and 602 patients (58·9%) were categorised as ever-smokers and the remaining as never-smokers. Kaplan-Meier survival estimates revealed that ever-smokers had a significant shorter median overall survival (OS) at 17·2 months [95% CI (14·9;19·1)] compared to never-smokers at 24·5 months (95% CI [19·2;30·7]). Multivariate analysis revealed smoking status as a significant prognostic factor for inferior OS with a hazard ratio (HR) of 1·22 [95% CI (1·04;1·44)]. In conclusion, smoking status was found to be associated with inferior OS in intensively treated AML patients.


Assuntos
Leucemia Mieloide Aguda/complicações , Fumar/efeitos adversos , Adolescente , Adulto , Idoso , Dinamarca , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
9.
Blood ; 123(6): 894-904, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24363398

RESUMO

Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in identifying expression changes fundamental to disease etiology. Here we present a method that facilitates the comparison of any cancer sample to its nearest normal cellular counterpart, using acute myeloid leukemia (AML) as a model. We first generated a gene expression-based landscape of the normal hematopoietic hierarchy, using expression profiles from normal stem/progenitor cells, and next mapped the AML patient samples to this landscape. This allowed us to identify the closest normal counterpart of individual AML samples and determine gene expression changes between cancer and normal. We find the cancer vs normal method (CvN method) to be superior to conventional methods in stratifying AML patients with aberrant karyotype and in identifying common aberrant transcriptional programs with potential importance for AML etiology. Moreover, the CvN method uncovered a novel poor-outcome subtype of normal-karyotype AML, which allowed for the generation of a highly prognostic survival signature. Collectively, our CvN method holds great potential as a tool for the analysis of gene expression profiles of cancer patients.


Assuntos
Biomarcadores Tumorais/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/genética , Western Blotting , Estudos de Casos e Controles , Seguimentos , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
10.
Nucleic Acids Res ; 41(Database issue): D1034-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23143109

RESUMO

The HemaExplorer (http://servers.binf.ku.dk/hemaexplorer) is a curated database of processed mRNA Gene expression profiles (GEPs) that provides an easy display of gene expression in haematopoietic cells. HemaExplorer contains GEPs derived from mouse/human haematopoietic stem and progenitor cells as well as from more differentiated cell types. Moreover, data from distinct subtypes of human acute myeloid leukemia is included in the database allowing researchers to directly compare gene expression of leukemic cells with those of their closest normal counterpart. Normalization and batch correction lead to full integrity of the data in the database. The HemaExplorer has comprehensive visualization interface that can make it useful as a daily tool for biologists and cancer researchers to assess the expression patterns of genes encountered in research or literature. HemaExplorer is relevant for all research within the fields of leukemia, immunology, cell differentiation and the biology of the haematopoietic system.


Assuntos
Bases de Dados Genéticas , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/genética , Animais , Humanos , Internet , Leucemia Mieloide Aguda/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Transcriptoma
11.
Blood ; 129(6): 662-663, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28183744
12.
Cell Rep ; 43(7): 114475, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38996072

RESUMO

Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN+ long-term repopulating HSCs (LT-HSCs; CD150+CD48-LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN- LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN+ LT-HSCs were more quiescent compared to EMCN- LT-HSCs. Emcn-/- and Emcn+/+ mice displayed comparable steady-state hematopoiesis, as well as frequencies, transcriptional programs, and long-term multi-lineage repopulating capacity of their LT-HSCs. Complementary functional analyses further revealed increased cell cycle entry upon treatment with 5-fluorouracil and reduced granulocyte colony-stimulating factor (GCSF) mobilization of Emcn-/- LT-HSCs, demonstrating that EMCN expression by LT-HSCs associates with quiescence in response to hematopoietic stress and is indispensable for effective LT-HSC mobilization. Transplantation of wild-type bone marrow cells into Emcn-/- or Emcn+/+ recipients demonstrated that EMCN is essential for endothelial cell-dependent maintenance/self-renewal of the LT-HSC pool and sustained blood cell production post-transplant.


Assuntos
Linhagem da Célula , Hematopoese , Células-Tronco Hematopoéticas , Animais , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Camundongos , Camundongos Endogâmicos C57BL , Movimento Celular , Fluoruracila/farmacologia , Humanos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Ciclo Celular , Células Endoteliais/metabolismo
13.
Leukemia ; 37(3): 593-605, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36631623

RESUMO

Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.


Assuntos
Histona Desmetilases , Leucemia Mieloide Aguda , Animais , Feminino , Humanos , Camundongos , Diferenciação Celular , Linhagem Celular , Relevância Clínica , Histona Desmetilases/genética , Leucemia Mieloide Aguda/genética
14.
Mol Cancer Ther ; 21(5): 703-714, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35247918

RESUMO

Currently, the majority of patients with acute myeloid leukemia (AML) still die of their disease due to primary resistance or relapse toward conventional reactive oxygen species (ROS)- and DNA damage-inducing chemotherapy regimens. Herein, we explored the therapeutic potential to enhance chemotherapy response in AML, by targeting the ROS scavenger enzyme MutT homolog 1 (MTH1, NUDT1), which protects cellular integrity through prevention of fatal chemotherapy-induced oxidative DNA damage. We demonstrate that MTH1 is a potential druggable target expressed by the majority of patients with AML and the inv(16)/KITD816Y AML mouse model mimicking the genetics of patients with AML exhibiting poor response to standard chemotherapy (i.e., anthracycline & cytarabine). Strikingly, combinatorial treatment of inv(16)/KITD816Y AML cells with the MTH1 inhibitor TH1579 and ROS- and DNA damage-inducing standard chemotherapy induced growth arrest and incorporated oxidized nucleotides into DNA leading to significantly increased DNA damage. Consistently, TH1579 and chemotherapy synergistically inhibited growth of clonogenic inv(16)/KITD816Y AML cells without substantially inhibiting normal clonogenic bone marrow cells. In addition, combinatorial treatment of inv(16)/KITD816Y AML mice with TH1579 and chemotherapy significantly reduced AML burden and prolonged survival compared with untreated or single treated mice. In conclusion, our study provides a rationale for future clinical studies combining standard AML chemotherapy with TH1579 to boost standard chemotherapy response in patients with AML. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiotherapies might benefit therapeutically from complementary treatment with TH1579.


Assuntos
Leucemia Mieloide Aguda , Nucleotídeos , Animais , Dano ao DNA , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Estresse Oxidativo , Pirimidinas , Espécies Reativas de Oxigênio , Saneamento
15.
Cancer Res ; 82(11): 2141-2155, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35311954

RESUMO

The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases. SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its autoinhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RAS/ERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD (internal tandem duplication)-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-cell acute lymphoblastic leukemia cell line and in the inv(16)/KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications. SIGNIFICANCE: These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD-positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Piperidinas , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Pirimidinas , Regulação Alostérica , Animais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Mutação , Fosforilação , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Tirosina/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
16.
Nat Commun ; 13(1): 3595, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35739121

RESUMO

Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues, and requires the coordinated induction of lineage-specific transcriptional programs and cell cycle withdrawal. To understand the underlying regulatory mechanisms of this fundamental process, we investigated how the tissue-specific transcription factors, CEBPA and CEBPE, coordinate cell cycle exit and lineage-specification in vivo during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-specification by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with differentiation through the use of distinct gene regulatory elements.


Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição , Animais , Ciclo Celular , Diferenciação Celular/genética , Granulócitos/metabolismo , Mamíferos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Clin Epidemiol ; 14: 225-237, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35241936

RESUMO

INTRODUCTION: The diagnosis of a life-threatening disease can lead to depression and anxiety resulting in pharmacological treatment. However, use of psychotropic drugs (antidepressants, anxiolytics, and antipsychotics) in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) is undetermined. METHODS: Prescription of psychotropic drugs in Danish AML and MDS patients was compared to a cohort matched on age, sex, and country of origin from the Danish background population using national population-based registries. RESULTS: In total, 2404 AML patients (median age 69 years) and 1307 MDS patients (median age 75 years) were included and each matched to five comparators from the background population. Two-year cumulative incidences showed that AML (20.6%) and MDS (21.2%) patients had a high risk of redemption of a psychotropic drug prescription compared to the background population (7.0% and 7.9%). High age, low educational level, and Charlson Comorbidity Index score ≥1 was associated with a higher risk in AML and MDS patients. Furthermore, non-curative treatment intent and performance status in AML patients, and high risk MDS were associated with elevated risk of psychotropic drug prescription. CONCLUSION: In conclusion, diagnoses of AML and MDS were associated with a higher rate of psychotropic drugs prescription compared to the background population.

18.
J Exp Med ; 202(1): 85-96, 2005 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-15983063

RESUMO

CCAAT/enhancer binding protein (C/EBP)alpha is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBP alpha to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations--all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count--normally associated with AML-were absent. These results show that disrupting the cell cycle regulatory function of C/EBP alpha is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/fisiologia , Ciclo Celular/fisiologia , Granulócitos/citologia , Células Progenitoras Mieloides/citologia , Neutrófilos/citologia , Animais , Transplante de Medula Óssea , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Ciclo Celular/genética , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Fenótipo
19.
Cancer Drug Resist ; 4(4): 984-995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35582388

RESUMO

Resistance of cancer patients to DNA damaging radiation therapy and chemotherapy remains a major problem in the clinic. The current review discusses the molecular mechanisms of therapy resistance in acute myeloid leukemia (AML) conferred by cooperative chemotherapy-induced DNA damage response (DDR) and mutational activation of PI3K/AKT signaling. In addition, strategies to overcome resistance are discussed, with particular focus on studies underpinning the vast potential of therapies combining standard chemotherapy AML regimens with small molecule inhibitors targeting key regulatory hubs at the interface of DDR and oncogenic signaling pathways.

20.
Leukemia ; 35(7): 2030-2042, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33299144

RESUMO

Most AML patients exhibit mutational activation of the PI3K/AKT signaling pathway, which promotes downstream effects including growth, survival, DNA repair, and resistance to chemotherapy. Herein we demonstrate that the inv(16)/KITD816Y AML mouse model exhibits constitutive activation of PI3K/AKT signaling, which was enhanced by chemotherapy-induced DNA damage through DNA-PK-dependent AKT phosphorylation. Strikingly, inhibitors of either PI3K or DNA-PK markedly reduced chemotherapy-induced AKT phosphorylation and signaling leading to increased DNA damage and apoptosis of inv(16)/KITD816Y AML cells in response to chemotherapy. Consistently, combinations of chemotherapy and PI3K or DNA-PK inhibitors synergistically inhibited growth and survival of clonogenic AML cells without substantially inhibiting normal clonogenic bone marrow cells. Moreover, treatment of inv(16)/KITD816Y AML mice with combinations of chemotherapy and PI3K or DNA-PK inhibitors significantly prolonged survival compared to untreated/single-treated mice. Mechanistically, our findings implicate that constitutive activation of PI3K/AKT signaling driven by mutant KIT, and potentially other mutational activators such as FLT3 and RAS, cooperates with chemotherapy-induced DNA-PK-dependent activation of AKT to promote survival, DNA repair, and chemotherapy resistance in AML. Hence, our study provides a rationale to select AML patients exhibiting constitutive PI3K/AKT activation for simultaneous treatment with chemotherapy and inhibitors of DNA-PK and PI3K to improve chemotherapy response and clinical outcome.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mutação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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