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Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

ABSTRACT: Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

PROVIDER: PRJNA737115 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14794085.fastq.gz	Fastqsanger.gz
	SRR14794086.fastq.gz	Fastqsanger.gz
	SRR14794087.fastq.gz	Fastqsanger.gz
	SRR14794088.fastq.gz	Fastqsanger.gz
	SRR14794089.fastq.gz	Fastqsanger.gz

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Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

Project description:The development of different generations of BCR-ABL1 tyrosine kinases inhibitors (TKIs) has led the overall survival (OS) of the chronic myeloid leukemia (CML) patients to become almost similar to that of a control population without leukemia, but the TKI therapy can be successfully discontinued only in half of those who are achieving a deep molecular response, that eans in approximately 15-20% of the entire population. In addition, although few, there are CML patients who show resistance to TKI therapy, are prone to progress to more advanced phases of the disease and die of CML related causes. Therefore, implementing an alternative approach for targeting TKI resistant leukemic cells would be of the essence in trying to solve these problems. Dihydroorotate dehydrogenase (DHODH) is a druggable enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML CD34+ cells and CML cell lines are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activated the apoptotic pathway and suppressed cell growth of CML cells in vitro and in vivo in a xenograft mice model. Moreover, inhibition of DHODH led to the reduction of amino acids and induction of huge metabolic stress in CML CD34+. Altogether, our study shows that targeting pyrimidine synthesis is a promising approach for targeting CML stem/progenitor cells, helping more patients to achieve good molecular response and possibly successful treatment discontinuation.

2022-07-06 | GSE177485 | GEO

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia.

Project description:The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy.

| S-EPMC9247109 | biostudies-literature

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.

Project description:Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.

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Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase

Project description:Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase

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SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

Project description:We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.

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Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shOPA1]

Project description:Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shOPA1]

| PRJNA918401 | ENA

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shMFN2]

Project description:Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shMFN2]

| PRJNA918402 | ENA

Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells

Project description:Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells

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Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia

Project description:Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia

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Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shOPA1]

Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.

2023-03-16 | GSE222168 | GEO

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