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Circadian Molecular Clock in Myeloid Malignancies – a novel therapeutic window?
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Os ritmos circadianos regulam várias funções fisiológicas do organismo e têm padrões oscilatórios de aproximadamente 24 horas. São controlados pela maquinaria do relógio molecular circadiano que consiste numa rede de genes que se baseia em ciclos de feedback transcricional-traducional. Este relógio modula a expressão génica de processos celulares importantes e interage com reguladores oncogénicos, estando a sua disrupção associada ao desenvolvimento do cancro.
As doenças malignas mieloides, incluindo a leucemia mieloide crónica, as neoplasias mieloproliferativas e a leucemia mieloide aguda, são caracterizadas pela ativação aberrante de vias oncogénicas. A relação entre a perturbação do ritmo circadiano e as vias oncogénicas nas doenças malignas mieloides ainda não está totalmente esclarecida.
O principal objetivo deste estudo foi investigar a interação entre a maquinaria do relógio molecular circadiano e as vias de sinalização oncogénicas, especificamente na via JAK-STAT. Foram utilizadas três linhas celulares derivadas de tumores malignos mieloides, K562, SET-2 e MOLM13. Estas linhas celulares possuem as mutações genéticas BCR-ABL1, JAK2V617F, e FLT3-ITD, e dependem de uma única via de ativação, o que as torna modelos perfeitos para estudar estas interações.
Para explorar o impacto da disrupção do relógio molecular circadiano na sinalização oncogénica, gerámos linhas celulares que visavam a inativação dos genes BMAL1 e CLOCK utilizando a tecnologia CRISPR/Cas9. Os nossos resultados indicam que a desregulação circadiana teve efeitos heterogéneos na via JAK-STAT nas diferentes linhas celulares. Além disso, a modulação farmacológica do relógio molecular circadiano com SR9011 levou a um aumento da expressão dos genes relacionados com a via JAK-STAT. Além disso, foi observada uma redução sinérgica da viabilidade celular quando o SR9011 foi combinado com inibidores específicos da via de sinalização. Estes resultados parecem indicar que tendo como alvo o relógio molecular circadiano e as vias oncogénicas, estes poderão constituir uma potencial abordagem terapêutica para tratar estas doenças malignas.
Os nossos resultados sugerem uma interação recíproca entre o relógio molecular circadiano e a sinalização oncogénica em doenças malignas mieloides.
The circadian rhythms regulate various physiological functions in the body and have oscillatory patterns of approximately 24 hours. These are controlled by the circadian molecular clock machinery that consists of a gene network that relies on transcriptional-translational feedback loops. This clock modulates the gene expression of important cellular processes and interacts with oncogenic regulators, and its disruption is associated with cancer development. Myeloid malignancies, including chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, are characterized by aberrant activation of oncogenic pathways. The relationship between circadian rhythm disruption and oncogenic pathways in myeloid malignancies is not yet fully understood. The main objective of this study was to investigate the interplay between the circadian molecular clock machinery and oncogenic signaling pathways, focusing specifically on the JAK-STAT pathway. Three cell lines of myeloid malignancies were used, K562, SET-2, and MOLM13. They carry the BCR-ABL1, JAK2V617F, and FLT3-ITD genetic mutations and rely on a single activation pathway making them the perfect models to study these interactions. To explore the impact of circadian disruption on oncogenic signaling, we generated cell lines with genetic inactivation of BMAL1 and CLOCK genes using the CRISPR/Cas9 technology. Our results indicated that circadian disruption had heterogeneous effects on the JAK-STAT pathway across the different cell lines. Furthermore, pharmacological modulation of the circadian molecular clock with SR9011 led to an increase in expression of JAK-STAT pathway-related genes. Moreover, a synergistic reduction in cell viability was observed when SR9011 was combined with pathway-specific inhibitors. These results may indicate that targeting the circadian molecular clock and the oncogenic pathways might constitute a potential therapeutic approach to treat these malignancies. Our findings suggest a reciprocal interaction between the circadian molecular clock and oncogenic signaling in myeloid malignancies.
The circadian rhythms regulate various physiological functions in the body and have oscillatory patterns of approximately 24 hours. These are controlled by the circadian molecular clock machinery that consists of a gene network that relies on transcriptional-translational feedback loops. This clock modulates the gene expression of important cellular processes and interacts with oncogenic regulators, and its disruption is associated with cancer development. Myeloid malignancies, including chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, are characterized by aberrant activation of oncogenic pathways. The relationship between circadian rhythm disruption and oncogenic pathways in myeloid malignancies is not yet fully understood. The main objective of this study was to investigate the interplay between the circadian molecular clock machinery and oncogenic signaling pathways, focusing specifically on the JAK-STAT pathway. Three cell lines of myeloid malignancies were used, K562, SET-2, and MOLM13. They carry the BCR-ABL1, JAK2V617F, and FLT3-ITD genetic mutations and rely on a single activation pathway making them the perfect models to study these interactions. To explore the impact of circadian disruption on oncogenic signaling, we generated cell lines with genetic inactivation of BMAL1 and CLOCK genes using the CRISPR/Cas9 technology. Our results indicated that circadian disruption had heterogeneous effects on the JAK-STAT pathway across the different cell lines. Furthermore, pharmacological modulation of the circadian molecular clock with SR9011 led to an increase in expression of JAK-STAT pathway-related genes. Moreover, a synergistic reduction in cell viability was observed when SR9011 was combined with pathway-specific inhibitors. These results may indicate that targeting the circadian molecular clock and the oncogenic pathways might constitute a potential therapeutic approach to treat these malignancies. Our findings suggest a reciprocal interaction between the circadian molecular clock and oncogenic signaling in myeloid malignancies.
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Circadian Molecular Clock Myeloid Malignancies Signaling pathways CRISPR/Cas9