Molecular Approaches to Treating Pediatric Leukemias

Kuhlen, Michaela; Klusmann, Jan‐Henning; Hoell, Jessica I.

doi:10.3389/fped.2019.00368

Cited by 30 publications

(32 citation statements)

References 122 publications

(138 reference statements)

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“…Different inhibitors of the Akt/mTOR axis have been studied in AML and demonstrated to have cytotoxic activity [ 74 ]. Inhibitors of the mTORC1 complex, the previously cited rapalogs, showed promising results, evidenced in a study conducted by treating AML primary blasts with Everolimus [ 75 ]. Nonetheless, to date, these drugs used in combination with chemotherapy in clinical trials for refractory/relapsed patients have not confirmed the expected preclinical results [ 61 ].…”

Section: Current Knowledge On Pediatric Acute Leukemiamentioning

confidence: 99%

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

Anselmi

Bertuccio

Lonetti

et al. 2020

IJMS

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Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.

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Section: Current Knowledge On Pediatric Acute Leukemiamentioning

confidence: 99%

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

Anselmi

Bertuccio

Lonetti

et al. 2020

IJMS

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“…However, a proportion of patients still shows no response to existing therapeutic drugs and suffered from the side-effects of long-term multi-drug treatment. In addition, existing therapeutic drugs cannot further improve the prognosis of refractory and relapsed B-ALL ( Kuhlen et al, 2019 ). Therefore, new strategies for the treatment of B-ALL should be identified.…”

Section: Introductionmentioning

confidence: 99%

CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism

Huang

Abudureheman

Xia

et al. 2021

Front. Cell Dev. Biol.

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B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.

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“…With recent advances in multi-modal chemotherapy regimens, the 5-year overall survival has reached 90% in children with B-ALL, whereas the outcome of older patients (≥40 years) remains poor (1). Moreover, the refractory and relapsed B-ALL patients show no response to existing therapeutic drugs, and a proportion of patients cannot tolerate the sideeffects of multi-drug combination therapy (2). Therefore, identifying new alternative drugs for the treatment of B-ALL is necessary.…”

Section: Introductionmentioning

confidence: 99%

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

Abudureheman

Xia

et al. 2021

Front. Oncol.

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B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.

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Molecular Approaches to Treating Pediatric Leukemias

Cited by 30 publications

References 122 publications

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

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