Drug Information

Drug (ID: DG00338) and It's Reported Resistant Information

• Name: Rituximab
• Indication:
  In total 2 Indication(s)
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Approved; [1]
  Pemphigus [ICD-11: EB40]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  B cell lymphoma [ICD-11: 2A86]; [3]
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [4]
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; [1]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [5]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; [6]
• Target: Leukocyte surface antigen Leu-16 (CD20); CD20_HUMAN; [1]
• TTD Drug ID: D0YM7U
• DrugBank ID: DB00073

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Diffuse large B-cell lymphoma [ICD-11: 2A81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: B-lymphocyte antigen CD20 (CD20) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

Key Molecule: Pyruvate dehydrogenase kinase 4 (PDK4) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-miR-125b-5p [1]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SU-DHL-2 cells; Pleural effusion; Homo sapiens (Human); CVCL_9550
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.

Key Molecule: hsa-miR-99a-5p [1]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SU-DHL-2 cells; Pleural effusion; Homo sapiens (Human); CVCL_9550
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glutathione peroxidase 4 (GPX4) [7]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SLC7A11/GSH/GPX4 signaling pathway; Regulation; N.A.
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• Experiment for Molecule Alteration: Western blot assay; GSH assay; MDA assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. The SLC7A11/GSH/GPX4 signal transduction axis is the core pathway of ferroptosis, and SLC7A11 plays a major transport function in the cystine/glutamate anti-transporter (Xc-system). The extracellular cysteine is imported into the cell through the XC- system and then converted to cysteine to synthesize GSH. GPX4 uses reduced GSH as a cofactor to detoxify lipid peroxides into lipid alcohols, thereby preventing ferroptosis induced in cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-370-3p [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: hsa-miR-381-3p [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: hsa-miR-409-3p [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: hsa-mir-199a [9]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• In Vitro Model: Karpas-422 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1325
• In Vitro Model: RI-1 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1885
• In Vitro Model: U2932 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1896
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.

Key Molecule: hsa-mir-497 [9]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• In Vitro Model: Karpas-422 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1325
• In Vitro Model: RI-1 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1885
• In Vitro Model: U2932 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_1896
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Inositol monophosphatase 1 (IMPA1) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: PI3-kinase delta (PIK3CD) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: PI3-kinase gamma (PIK3CG) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [8]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Chronic lymphocytic leukemia [ICD-11: 2A82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 17p13 (Unclear) [4]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Structural variation; Copy number loss
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: FISH assay
• Experiment for Drug Resistance: Multivariable Andersen-Gill regression analysis; VH sequencing assay
• Mechanism Description: Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [10]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Notch signaling pathway; Activation; hsa04330
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Mutations in NOTCH1 result in increased stability of an activated intracellular NOTCH1 isoform, which confers cell survival and apoptosis resistance, in part by sustaining expression of the anti-apoptotic protein Mcl-1, and promoting the activity of the key translational regulator eIF4E. Compared with wild-type cases, NOTCH1-mutated cases have progressive disease and significantly shorter survival, and demonstrate resistance to the anti-CD20 monoclo.l antibody rituximab, a phenotype thought to be associated with the low CD20 levels and dysregulation of histone deacetylases(HDAC)-mediated epigenetic repression of CD20 expression observed in NOTCH1-mutated CLL.

Key Molecule: Cellular tumor antigen p53 (TP53) [11]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole exome sequencing assay; Targeted deep sequencing assay; Sanger sequencing assay
• Mechanism Description: Following exposure to chemoimmunotherapy, the resistant TP53 aberrant clones accumulate and dominate the tumour.

B cell lymphoma [ICD-11: 2A86]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: B-lymphocyte antigen CD20 (CD20) [3]

• Resistant Disease: B cell lymphoma [ICD-11: 2A86.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Obviously, the CD20 molecule itself can be involved in resistance to Rituximab by loss in protein expression, membrane exposure and structural changes. Reduction or loss of CD20 cell surface expression following Rituximab treatment has been reported in some patients with B-NHL.

References

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• Ref 6: Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20. Cancer Sci. 2021 Sep;112(9):3585-3597.
• Ref 7: Rituximab induces ferroptosis and RSL3 overcomes rituximab resistance in diffuse large B-cell lymphoma cells. Arch Biochem Biophys. 2024 Nov;761:110188.
• Ref 8: MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma. Blood Cancer J. 2017 Dec 15;7(12):654. doi: 10.1038/s41408-017-0033-8.
• Ref 9: miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients. Int J Mol Sci. 2015 Aug 5;16(8):18077-95. doi: 10.3390/ijms160818077.
• Ref 10: The mutational signature of chronic lymphocytic leukemia. Biochem J. 2016 Nov 1;473(21):3725-3740. doi: 10.1042/BCJ20160256.
• Ref 11: Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease. Leukemia. 2016 Jun;30(6):1301-10. doi: 10.1038/leu.2016.10. Epub 2016 Feb 5.