RESUMO
BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve - eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Proteólise , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-abl/metabolismo , Animais , Quimera de Direcionamento de ProteóliseRESUMO
BACKGROUND: BCR::ABL1-like or Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) was first reported in 2009. Ph-like ALL is characterized by gene signature similar to Philadelphia chromosome ALL, but without BCR::ABL1 fusions. Molecularly, Ph-like ALL is divided into seven categories, with CRLF2 and ABL-class rearrangements being the two most common subtypes, exhibiting alterations in distinct downstream signaling cascades. CASE PRESENTATION: We report a rare case of pediatric Ph-like ALL with concomitant CRLF2 and ABL1 rearrangements. CRLF2 was fused with P2RY8, its most common fusion partner, whereas ABL1 was fused with MYO18B, a novel fusion partner that has not been previously reported. The 4-year-old female patient was treated using the national multicenter CCCG-ALL-2020 protocol with the addition of dasatinib at the end of induction when ABL1 rearrangement was confirmed by RNA-seq. Morphologically and molecularly, the patient remained in continuous remission until the last follow-up. To the best of our knowledge, this is the first case of Ph-like ALL harboring two distinct rearrangement categories. CONCLUSIONS: Our results identified that ABL1 rearrangement and CRLF2 rearrangement can coexist. The application of FISH, whole transcription sequencing, PCR can help us to have a more comprehensive understanding of ALL cytogenetics and molecular biology. Further studies are needed to explore the role of targeted therapies in such rare clinical scenarios.
Assuntos
Rearranjo Gênico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Citocinas , Humanos , Feminino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , Receptores de Citocinas/genética , Proteínas Proto-Oncogênicas c-abl/genéticaAssuntos
Resistencia a Medicamentos Antineoplásicos , Éxons , Proteínas de Fusão bcr-abl , Humanos , Proteínas de Fusão bcr-abl/genética , Resistencia a Medicamentos Antineoplásicos/genética , Éxons/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Domínios de Homologia de src , Proteínas Proto-Oncogênicas c-abl/genética , Conformação Proteica , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Niacinamida/análogos & derivadosRESUMO
BACKGROUND: Alpha-synucleinopathies are incurable neurodegenerative diseases. Abelson tyrosine kinase inhibitors (Abl TKIs) may be disease-modifying therapies. This systematic review, meta-analysis, and meta-regression evaluated the use of Abl TKIs in their treatment. METHODS: We searched PubMed, Embase, and Cochrane databases for trials using Abl TKIs in patients with Parkinson's disease and Lewy body dementia published until July 2023. The outcome was the change in the MDS-UPDRS-III (Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale III). DerSimonian-Laird random-effects model was used to calculate the pooled effect estimates. Leave-one-out forest plots were used for the sensitivity analysis, and meta-regression (restricted maximum likelihood) was performed. RESULTS: Five studies (197 patients) were included. Nilotinib 300 mg had an effect size of -1.154 (95% confidence interval [CI], -3.000 to 0.692). Nilotinib 150 mg and bosutinib 100 mg versus placebo yielded 0.82 (95% CI, -3.76 to 5.41). Sensitivity analysis showed that 1 trial changed the significance of the nilotinib 300 mg single-arm analysis (MD = -1.723; 95% CI, -2.178 to -1.268). Meta-regression revealed that lower age (EC = -0.9103, SE = 0.2286, P < 0.0001) and higher baseline MDS-UPDRS-III scores (EC = 0.1210, SE = 0.0168, P < 0.0001) could explain the inefficacy of nilotinib 300 mg. CONCLUSIONS: Nilotinib (300 mg) proved effective postsensitivity analysis, unlike lower doses and bosutinib in Parkinson's disease/Lewy body dementia. Abl TKIs showed reduced efficacy in younger, more impaired patients, indicating the need for further testing with higher-potency drugs in patients who have diseases that are in the early stage but with a later onset.
Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Inibidores de Proteínas Quinases , Humanos , Doença de Parkinson/tratamento farmacológico , Doença por Corpos de Lewy/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Compostos de Anilina/uso terapêutico , Nitrilas/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Quinolinas/uso terapêuticoAssuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Isoformas de Proteínas , Humanos , Proteínas de Fusão bcr-abl/genética , Resistencia a Medicamentos Antineoplásicos/genética , Isoformas de Proteínas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Niacinamida/análogos & derivados , PirazóisRESUMO
Despite the success of AlphaFold methods in predicting single protein structures, these methods showed intrinsic limitations in the characterization of multiple functional conformations of allosteric proteins. The recent NMR-based structural determination of the unbound ABL kinase in the active state and discovery of the inactive low-populated functional conformations that are unique for ABL kinase present an ideal challenge for the AlphaFold2 approaches. In the current study, we employ several adaptations of the AlphaFold2 methodology to predict protein conformational ensembles and allosteric states of the ABL kinase including randomized alanine sequence scanning combined with the multiple sequence alignment subsampling proposed in this study. We show that the proposed new AlphaFold2 adaptation combined with local frustration profiling of conformational states enables accurate prediction of the protein kinase structures and conformational ensembles, also offering a robust approach for interpretable characterization of the AlphaFold2 predictions and detection of hidden allosteric states. We found that the large high frustration residue clusters are uniquely characteristic of the low-populated, fully inactive ABL form and can define energetically frustrated cracking sites of conformational transitions, presenting difficult targets for AlphaFold2. The results of this study uncovered previously unappreciated fundamental connections between local frustration profiles of the functional allosteric states and the ability of AlphaFold2 methods to predict protein structural ensembles of the active and inactive states. This study showed that integration of the randomized sequence scanning adaptation of AlphaFold2 with a robust landscape-based analysis allows for interpretable atomistic predictions and characterization of protein conformational ensembles, providing a physical basis for the successes and limitations of current AlphaFold2 methods in detecting functional allosteric states that play a significant role in protein kinase regulation.
Assuntos
Conformação Proteica , Proteínas Proto-Oncogênicas c-abl , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/metabolismo , Regulação Alostérica , Humanos , Modelos Moleculares , Sequência de AminoácidosAssuntos
Crise Blástica , Proteínas de Fusão bcr-abl , Células-Tronco Neoplásicas , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Crise Blástica/patologia , Crise Blástica/tratamento farmacológico , Humanos , Animais , Camundongos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/genética , Niacinamida/análogos & derivadosRESUMO
Germline gain of function variants in the oncogene ABL1 cause congenital heart defects and skeletal malformations (CHDSKM) syndrome. Whether a corresponding ABL1 deficiency disorder exists in humans remains unknown although developmental defects in mice deficient for Abl1 support this notion. Here, we describe two multiplex consanguineous families, each segregating a different homozygous likely loss of function variant in ABL1. The associated phenotype is multiple congenital malformations and distinctive facial dysmorphism that are opposite in many ways to CHDSKM. We suggest that a tight balance of ABL1 activity is required during embryonic development and that both germline gain of function and loss of function variants result in distinctively different allelic congenital malformation disorders.
Assuntos
Cardiopatias Congênitas , Proteínas Proto-Oncogênicas c-abl , Humanos , Cardiopatias Congênitas/genética , Feminino , Masculino , Proteínas Proto-Oncogênicas c-abl/genética , Linhagem , Fenótipo , Síndrome , Anormalidades Múltiplas/genética , Mutação em Linhagem GerminativaRESUMO
Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl's activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.
Assuntos
Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas c-abl , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/metabolismo , Modelos Moleculares , Proteínas Tirosina Quinases/metabolismo , Domínios de Homologia de src , Mesilato de Imatinib/farmacologiaRESUMO
BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34+ leukemic stem/progenitor cells using 100 single drugs and TKI-drug combinations and identify sensitivities to Wee1, MDM2, and BCL2 inhibitors. These agents effectively inhibit primitive CD34+CD38- CML cells and demonstrate potent synergies when combined with TKIs. Flow-cytometry-based drug screening identifies mepacrine to induce differentiation of CD34+CD38- cells. We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Sistemas CRISPR-Cas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Linhagem Celular TumoralRESUMO
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.
Assuntos
Pilocarpina , Proteínas Proto-Oncogênicas c-abl , Convulsões , Animais , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/patologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologiaRESUMO
A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, 1H-, 13C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC50 of 0.018 µM for normoxia, and 0.001 µM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC500.25 µM and Abl inhibitory activity with IC500.08 µM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC500.31 µM, VEGFR-2 IC500.68 µM, B-raf IC500.33 µM, ERK IC501.41 µM, CK1 IC500.29 µM and p38-MAPK IC500.38 µM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability.
Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-abl , Quinases da Família src , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Guanidina/farmacologia , Guanidina/química , Guanidina/síntese química , Guanidina/análogos & derivados , Células HL-60 , Leucemia/tratamento farmacológico , Leucemia/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo , Relação Estrutura-Atividade , Cianamida/síntese química , Cianamida/química , Cianamida/farmacologiaRESUMO
BACKGROUND: Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood. METHODS: To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts. RESULTS: In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis. CONCLUSIONS: Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.
Assuntos
Fibroblastos , Fibrose , Miofibroblastos , Proteínas Proto-Oncogênicas c-abl , Receptores de Quinase C Ativada , Transdução de Sinais , Animais , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Humanos , Camundongos , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptores de Quinase C Ativada/genética , Receptores de Quinase C Ativada/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Rim/patologia , Rim/metabolismo , Masculino , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
ABSTRACT: Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Trifosfato de Adenosina/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/química , Niacinamida/análogos & derivados , PirazóisAssuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , /uso terapêuticoRESUMO
OBJECTIVE: To describe the features of ETV6::ABL1 AML as well as the clinical treatment and outcomes. METHODS: Clinical data were collected from three patients diagnosed with ETV6::ABL1 AML at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital. Their clinical and laboratory features were analyzed, and the treatment process and outcomes were described. Ten reported cases of ETV6::ABL1 AML from the literature were also included for analysis. RESULTS: The median age of the patients was 34 years, and 2 patients were male. No patient had a history of blood disorders before diagnosis. After relapse, they were referred to our hospital, where the ETV6::ABL1 gene was detected. Unfortunately, Patient 1 died rapidly after leukemia relapse due to severe infection. Patients 2 and 3 received salvage therapy with a dasatinib-containing regimen, followed by allo-HSCT, and are currently alive and disease-free. CONCLUSION: ETV6::ABL1 is a rare but recurrent genetic aberration in AML, and the combined use of fluorescence in situ hybridization and PCR can better identify this fusion gene. Patients carrying ETV6::ABL1 have a high relapse rate and a poor prognosis. TKIs are a reasonable treatment option for this group, and allo-HSCT may be curative.
Assuntos
Variante 6 da Proteína do Fator de Translocação ETS , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas c-ets , Proteínas Repressoras , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Resultado do TratamentoAssuntos
Dasatinibe , Transplante de Células-Tronco Hematopoéticas , Humanos , Dasatinibe/uso terapêutico , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva , Proteínas Proto-Oncogênicas c-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adulto , Masculino , Transplante Homólogo , FemininoRESUMO
ABSTRACT: Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in â¼3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, each of which has up to 10 described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL with a similar gene expression profile, poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity in the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity within and among each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions for any of the 4 tyrosine kinase genes were relatively sensitive to imatinib. In contrast, the PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with the ALL immunophenotype, 5' fusion partner, presence or absence of Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant of TKI sensitivity and relevant for specific TKI selection.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-abl , Domínios de Homologia de src , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Criança , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Adolescente , Pré-Escolar , Feminino , Masculino , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Dasatinibe/uso terapêutico , Dasatinibe/farmacologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Parkinson's disease (PD) is the second-most prevalent central nervous system (CNS) neurodegenerative condition. Over the past few decades, suppression of BCR-Abelson tyrosine kinase (c-Abl), which serves as a marker of -synuclein aggregation and oxidative stress, has shown promise as a potential therapy target in PD. c-Abl inhibition has the potential to provide neuroprotection against PD, as shown by experimental results and the first-in-human trial, which supports the strategy in bigger clinical trials. Furthermore, glutamate receptors have also been proposed as potential therapeutic targets for the treatment of PD since they facilitate and regulate synaptic neurotransmission throughout the basal ganglia motor system. It has been noticed that pharmacological manipulation of the receptors can change normal as well as abnormal neurotransmission in the Parkinsonian brain. The review study contributes to a comprehensive understanding of the approach toward the role of c-Abl and glutamate receptors in Parkinson's disease by highlighting the significance and urgent necessity to investigate new pharmacotherapeutic targets. The article covers an extensive insight into the concept of targeting, pathophysiology, and c-Abl interaction with α-synuclein, parkin, and cyclin-dependent kinase 5 (Cdk5). Furthermore, the concepts of Nmethyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) receptor, and glutamate receptors are discussed briefly. Conclusion: This review article focuses on in-depth literature findings supported by an evidence-based discussion on pre-clinical trials and clinical trials related to c-Abl and glutamate receptors that act as potential therapeutic targets for PD.