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iNatureB-cell acute lymphoblastic leukemia (B-ALL) is a serious malignant hematopoietic disease that causes clonal expansion of hematopoietic stem/progenitor cells.
This phenomenon usually occurs in children/adolescents.
Several treatment options have been shown to achieve ideal results in the treatment of B-ALL, including chemotherapy, bone marrow (BM) transplantation, chimeric antigen receptor T cell (CAR-T) treatment or a combination of these treatments.
However, the effectiveness of the current strategy is affected by drug resistance, lack of a source of donor hematopoietic stem cells (HSC) matched by the main histocompatibility complex, patient anergy, or toxicity caused by CAR-T therapy.
How the metabolic state controls the fate of different types of leukemia cells remains elusive.
On March 10, 2021, Zheng Junke from Shanghai Jiaotong University, Zhigang Lu from Fudan University, Yuzheng Zhao from East China University of Science and Technology, and Jun Xu from Tongji University jointly published an online publication titled "Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute" in Science Advances.
Lymphoblastic leukemia" research paper, using SoNar transgenic mouse strains, proved that B-cell acute lymphoblastic leukemia (B-ALL) cells have an advantage in the use of oxidative phosphorylation.
B-ALL cells with a low SoNar ratio (SoNar-low) have enhanced mitochondrial respiration, mainly located in the blood vessel wall, and have more functional leukemia initiating cells than SoNar-high cells in mouse B-ALL .
SoNar-low cells are more resistant to cytosine arabinoside (Ara-C) treatment.
Human primary B-ALL cells with low SoNar also prefer oxidative phosphorylation.
The inhibition of oxidative phosphorylation with several drugs is sufficient to attenuate the resistance induced by Ara-C.
This study provides a unique perspective for understanding the potential link between metabolism and the fate of B-ALL cells.
B-cell acute lymphoblastic leukemia (B-ALL) is a serious malignant hematopoietic disease that causes clonal expansion of hematopoietic stem/progenitor cells.
This phenomenon usually occurs in children/adolescents.
Several treatment options have been shown to achieve ideal results in the treatment of B-ALL, including chemotherapy, bone marrow (BM) transplantation, chimeric antigen receptor T cell (CAR-T) treatment or a combination of these treatments.
However, the effectiveness of the current strategy is affected by drug resistance, lack of a source of donor hematopoietic stem cells (HSC) matched by the main histocompatibility complex, patient anergy, or toxicity caused by CAR-T therapy.
Although chemotherapy is considered to be one of the most effective methods for the treatment of B-ALL, 20% of patients still relapse after treatment with cytarabine (Ara-C), anthracycline antibiotics or other chemotherapy drugs.
There is increasing evidence that a small group of leukemia initiating cells (LIC) may lead to drug resistance or recurrence of leukemia.
For example, the immunophenotype CD34+CD19+ LICs may be closely related to the leukemia progression and drug resistance of human B-ALL.
However, the specific markers showing the enrichment of B-ALL-LIC and the mechanism by which chemotherapy leads to drug resistance are still unknown.
Recently, it has been discovered that the metabolic state plays a key role in the occurrence of many different types of cancer, including hematology and solid cancer.
For example, it has been reported that mutations in isocitrate dehydrogenase 1/2 (IDH1/2) can cause many types of cancers, such as acute myeloid leukemia (AML), glioblastoma, and colon cancer.
Acute/chronic myeloid LICs mainly use glycolysis as an energy source.
Fructose metabolism enhances the proliferation of Ph + (Philadelphia chromosome positive)-B-ALL cells.
However, the precise metabolic profile of different nutrients in B-ALL is unclear, and it is unclear whether the metabolic status is closely related to drug resistance.
At present, the drug resistance of B-ALL cells is believed to be caused by many internal factors (such as transcription factors or epigenetic modifications) and changes in external factors.
For example, mutations in the transcription factor IKZF1 lead to a significant decrease in sensitivity to tyrosine inhibitor therapy in B-ALL cells.
Down-regulation of TWIST2 can also lead to resistance to the chemotherapy drugs etoposide, daunorubicin and dexamethasone.
However, how the unique metabolism of different nutrients promotes the drug resistance of B-ALL cells remains to be further studied.
Although some chemical dyes including TMRM (tetramethylrhodamine methyl ester), MitoTracker and H2DCFDA have been used to assess the mitochondrial activity and reactive oxygen levels in different types of leukemia cells, they indirectly reflect the metabolic status of leukemia cells.
The determination of intermediate metabolites by commercial kits is another way to assess metabolic status.
Nevertheless, only a limited number of metabolites can be measured routinely.
At present, it is still very challenging to conduct real-time sensitive and specific monitoring of the in vitro/in vivo dynamic changes of the metabolism of certain nutrients in a single leukemia cell or LIC.
Recently, it has been reported that the highly responsive reduced form of NADH/NAD + sensor (SoNar) has been used in living cells and in vivo metabolism studies.
SoNar is an intrinsic ratio sensor with two excitation wavelengths (420 and 485 nm), and its response to NADH and NAD + is the opposite change of the fluorescence ratio.
SoNar strictly responds to the NADH/NAD+ ratio, not the absolute concentration of either of the two nucleotides.
SoNar exhibits a dynamic range of 1500% at different NAD+/NADH ratios, making it one of the most rapidly responding genetically coded sensors currently available.
Therefore, it can better track subtle changes in cell metabolism in real time.
The SoNar sensor can be used to sensitively and specifically monitor the cytoplasmic NADH/NAD + level in vivo and in vitro, which is closely related to the energy metabolism of AML-LICs.
The study used the SoNar transgenic mouse strain to prove that B-cell acute lymphoblastic leukemia (B-ALL) cells have an advantage in the use of oxidative phosphorylation.
B-ALL cells with a low SoNar ratio (SoNar-low) have enhanced mitochondrial respiration, mainly located in the blood vessel wall, and have more functional leukemia initiating cells than SoNar-high cells in mouse B-ALL .
SoNar-low cells are more resistant to cytosine arabinoside (Ara-C) treatment.
Human primary B-ALL cells with low SoNar also prefer oxidative phosphorylation.
The inhibition of oxidative phosphorylation with several drugs is sufficient to attenuate the resistance induced by Ara-C.
This study provides a unique perspective for understanding the potential link between metabolism and the fate of B-ALL cells.
Reference message: https://advances.
sciencemag.
org/content/7/11/eabd6280
This phenomenon usually occurs in children/adolescents.
Several treatment options have been shown to achieve ideal results in the treatment of B-ALL, including chemotherapy, bone marrow (BM) transplantation, chimeric antigen receptor T cell (CAR-T) treatment or a combination of these treatments.
However, the effectiveness of the current strategy is affected by drug resistance, lack of a source of donor hematopoietic stem cells (HSC) matched by the main histocompatibility complex, patient anergy, or toxicity caused by CAR-T therapy.
How the metabolic state controls the fate of different types of leukemia cells remains elusive.
On March 10, 2021, Zheng Junke from Shanghai Jiaotong University, Zhigang Lu from Fudan University, Yuzheng Zhao from East China University of Science and Technology, and Jun Xu from Tongji University jointly published an online publication titled "Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute" in Science Advances.
Lymphoblastic leukemia" research paper, using SoNar transgenic mouse strains, proved that B-cell acute lymphoblastic leukemia (B-ALL) cells have an advantage in the use of oxidative phosphorylation.
B-ALL cells with a low SoNar ratio (SoNar-low) have enhanced mitochondrial respiration, mainly located in the blood vessel wall, and have more functional leukemia initiating cells than SoNar-high cells in mouse B-ALL .
SoNar-low cells are more resistant to cytosine arabinoside (Ara-C) treatment.
Human primary B-ALL cells with low SoNar also prefer oxidative phosphorylation.
The inhibition of oxidative phosphorylation with several drugs is sufficient to attenuate the resistance induced by Ara-C.
This study provides a unique perspective for understanding the potential link between metabolism and the fate of B-ALL cells.
B-cell acute lymphoblastic leukemia (B-ALL) is a serious malignant hematopoietic disease that causes clonal expansion of hematopoietic stem/progenitor cells.
This phenomenon usually occurs in children/adolescents.
Several treatment options have been shown to achieve ideal results in the treatment of B-ALL, including chemotherapy, bone marrow (BM) transplantation, chimeric antigen receptor T cell (CAR-T) treatment or a combination of these treatments.
However, the effectiveness of the current strategy is affected by drug resistance, lack of a source of donor hematopoietic stem cells (HSC) matched by the main histocompatibility complex, patient anergy, or toxicity caused by CAR-T therapy.
Although chemotherapy is considered to be one of the most effective methods for the treatment of B-ALL, 20% of patients still relapse after treatment with cytarabine (Ara-C), anthracycline antibiotics or other chemotherapy drugs.
There is increasing evidence that a small group of leukemia initiating cells (LIC) may lead to drug resistance or recurrence of leukemia.
For example, the immunophenotype CD34+CD19+ LICs may be closely related to the leukemia progression and drug resistance of human B-ALL.
However, the specific markers showing the enrichment of B-ALL-LIC and the mechanism by which chemotherapy leads to drug resistance are still unknown.
Recently, it has been discovered that the metabolic state plays a key role in the occurrence of many different types of cancer, including hematology and solid cancer.
For example, it has been reported that mutations in isocitrate dehydrogenase 1/2 (IDH1/2) can cause many types of cancers, such as acute myeloid leukemia (AML), glioblastoma, and colon cancer.
Acute/chronic myeloid LICs mainly use glycolysis as an energy source.
Fructose metabolism enhances the proliferation of Ph + (Philadelphia chromosome positive)-B-ALL cells.
However, the precise metabolic profile of different nutrients in B-ALL is unclear, and it is unclear whether the metabolic status is closely related to drug resistance.
At present, the drug resistance of B-ALL cells is believed to be caused by many internal factors (such as transcription factors or epigenetic modifications) and changes in external factors.
For example, mutations in the transcription factor IKZF1 lead to a significant decrease in sensitivity to tyrosine inhibitor therapy in B-ALL cells.
Down-regulation of TWIST2 can also lead to resistance to the chemotherapy drugs etoposide, daunorubicin and dexamethasone.
However, how the unique metabolism of different nutrients promotes the drug resistance of B-ALL cells remains to be further studied.
Although some chemical dyes including TMRM (tetramethylrhodamine methyl ester), MitoTracker and H2DCFDA have been used to assess the mitochondrial activity and reactive oxygen levels in different types of leukemia cells, they indirectly reflect the metabolic status of leukemia cells.
The determination of intermediate metabolites by commercial kits is another way to assess metabolic status.
Nevertheless, only a limited number of metabolites can be measured routinely.
At present, it is still very challenging to conduct real-time sensitive and specific monitoring of the in vitro/in vivo dynamic changes of the metabolism of certain nutrients in a single leukemia cell or LIC.
Recently, it has been reported that the highly responsive reduced form of NADH/NAD + sensor (SoNar) has been used in living cells and in vivo metabolism studies.
SoNar is an intrinsic ratio sensor with two excitation wavelengths (420 and 485 nm), and its response to NADH and NAD + is the opposite change of the fluorescence ratio.
SoNar strictly responds to the NADH/NAD+ ratio, not the absolute concentration of either of the two nucleotides.
SoNar exhibits a dynamic range of 1500% at different NAD+/NADH ratios, making it one of the most rapidly responding genetically coded sensors currently available.
Therefore, it can better track subtle changes in cell metabolism in real time.
The SoNar sensor can be used to sensitively and specifically monitor the cytoplasmic NADH/NAD + level in vivo and in vitro, which is closely related to the energy metabolism of AML-LICs.
The study used the SoNar transgenic mouse strain to prove that B-cell acute lymphoblastic leukemia (B-ALL) cells have an advantage in the use of oxidative phosphorylation.
B-ALL cells with a low SoNar ratio (SoNar-low) have enhanced mitochondrial respiration, mainly located in the blood vessel wall, and have more functional leukemia initiating cells than SoNar-high cells in mouse B-ALL .
SoNar-low cells are more resistant to cytosine arabinoside (Ara-C) treatment.
Human primary B-ALL cells with low SoNar also prefer oxidative phosphorylation.
The inhibition of oxidative phosphorylation with several drugs is sufficient to attenuate the resistance induced by Ara-C.
This study provides a unique perspective for understanding the potential link between metabolism and the fate of B-ALL cells.
Reference message: https://advances.
sciencemag.
org/content/7/11/eabd6280
