Disease Information

General Information of the Disease (ID: DIS00550)

• Name: Acute myeloid leukemia
• ICD: ICD-11: 2A60

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Arsenic trioxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NFE2-related factor 2 (NRF2) [1]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxidative stress response signaling pathway; Regulation; N.A.
• In Vitro Model: MV4-11 ATO-R C4 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MV4-11 ATO-R C6 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Apoptosis analysis; Intracellular ROS assay; Flow cytometry assay
• Mechanism Description: We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Key Molecule: B-cell lymphoma 2 (BCL2) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Key Molecule: Nucleolar protein 3 (NOL3) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Key Molecule: Interleukin-10 (IL10) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Key Molecule: CD70 antigen (CD70) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Key Molecule: Baculoviral IAP repeat-containing protein 3 (BIRC3) [2]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Amplification
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Transglutaminase 2 (TG2) [3]

• Metabolic Type: Redox metabolism
• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Sensitive Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Transglutaminase 2 (TG2) [3]

• Metabolic Type: Redox metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Tretinoin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.

Investigative Drug(s) 1 drug(s) in total

ATO-Digoxin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NFE2-related factor 2 (NRF2) [1]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Sensitive Drug: ATO-Digoxin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Oxidative stress response signaling pathway; Regulation; N.A.
• In Vivo Model: MV4-11 ATO-R C6 xenograft mice; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: In-vivo drug treatment assay
• Mechanism Description: We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

References

• Ref 1: Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia. Ann Hematol. 2024 Jun;103(6):1919-1929.
• Ref 2: Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors. Pharmaceuticals (Basel). 2024 Nov 14;17(11):1529.
• Ref 3: ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2. Int J Mol Sci. 2023 Jun 30;24(13):10938.