Disease Information

General Information of the Disease (ID: DIS00058)

• Name: Mature T-cell lymphoma
• ICD: ICD-11: 2A90

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Bortezomib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [1]

• Sensitive Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [1]

• Resistant Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Maternally expressed 3 (MEG3) [2]

• Sensitive Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SUP-T1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1714
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: MEG3 promotes the drug sensitivity of T-LBL to chemotherapeutic agents by affecting the PI3k/mTOR pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: WT1 associated protein (WTAP) [3]

• Sensitive Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: YTS cells; Pleural effusion; Homo sapiens (Human); CVCL_D324
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: WTAP enhanced dual-specificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. Deletion of WTAP impaired chemotherapy resistance to DDP in human NKTCL cells.

Cyclophosphamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [1]

• Resistant Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cyclophosphamide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Maternally expressed 3 (MEG3) [2]

• Sensitive Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cyclophosphamide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SUP-T1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1714
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: MEG3 promotes the drug sensitivity of T-LBL to chemotherapeutic agents by affecting the PI3k/mTOR pathway.

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [4]

• Resistant Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Molecule Alteration: Missense mutation; p.F317R
• Resistant Drug: Dasatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Tritiated thymidine incorporation assay
• Mechanism Description: Mutations may impair TkI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph+ acute lymphoblastic leukemia (ALL) (F317R).

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [1]

• Resistant Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [5]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CXCL12/CXCR4 signaling pathway; Activation; hsa04061
• In Vitro Model: MyLa cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: MF-Fs promote migration and chemoresistance of MyLa cells through CXCL12/CXCR4 signaling. Through the entire range of Doxo concentrations, MyLa cells cocultured with MF-Fs were significantly more resistant than MyLa cells cocultured with N-Fs.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [1]

• Resistant Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [6]

• Resistant Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ABCG2 upregulated cell proliferation, increased clonogenicity, increased invasive ability and decreased apoptosis, in vivo and in vitro, when cells were treated with gemcitabine.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [6]

• Resistant Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ABCG2 upregulated cell proliferation, increased clonogenicity, increased invasive ability and decreased apoptosis, in vivo and in vitro, when cells were treated with gemcitabine.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein zeta/delta 14-3-3 (YWHAZ) [7]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: YTS cells; Pleural effusion; Homo sapiens (Human); CVCL_D324
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Compared with YTS-gem cells, the level of Pro apoptotic protein Bax in YTS gem cells that down regulated 14-3-3-Zetawas significantly higher. In contrast, the levels of anti apoptotic proteins Bcl-2, Caspase-3, cleaved caspase-3 and cyclin D1 decreased significantly.

Key Molecule: Protein zeta/delta 14-3-3 (YWHAZ) [7]

• Resistant Disease: Extranodal NK/T-cell lymphoma [ICD-11: 2A90.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: YTS cells; Pleural effusion; Homo sapiens (Human); CVCL_D324
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: 14-3-3-Zeta was up regulated in YTS gem cells, 14-3-3-Zeta promote cell proliferation and invasion, 14-3-3-Zeta protein induced enktl resistance to gemcitabine through anti apoptotic pathway.

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

Compound 3144

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [8]

• Sensitive Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Missense mutation; p.G13D (c.38G>A)
• Sensitive Drug: Compound 3144
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS signaling pathway; Inhibition; hsa04014
• In Vitro Model: MEF cells; Bone marrow; Homo sapiens (Human); CVCL_M515
• In Vivo Model: Athymic nude Nu/Nu mouse PDX model; Mus musculus

MRK-003

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [9]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Missense mutation; p.R505C (c.1513C>T)
• Resistant Drug: MRK-003
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R505C (c.1513C>T) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [9]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Missense mutation; p.R465C (c.1393C>T)
• Resistant Drug: MRK-003
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R465C (c.1393C>T) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [9]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Missense mutation; p.R465H (c.1394G>A)
• Resistant Drug: MRK-003
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R465H (c.1394G>A) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [9]

• Resistant Disease: T-cell lymphoma [ICD-11: 2A60.3]
• Molecule Alteration: Missense mutation; p.R479Q (c.1436G>A)
• Resistant Drug: MRK-003
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T-ALL cells; Bone marrow; Homo sapiens (Human); CVCL_1736
• In Vitro Model: 293a cells; Fetal kidney; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: V-FITC apoptosis detection kit I assay
• Mechanism Description: The missense mutation p.R479Q (c.1436G>A) in gene FBXW7 cause the resistance of MRK-003 by unusual activation of pro-survival pathway

Investigative Drug(s) 3 drug(s) in total

5-FU-CDDP

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Small nucleolar RNA host gene 12 (SNHG12) [10]

• Resistant Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: 5-FU-CDDP
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• In Vitro Model: YTS cells; Pleural effusion; Homo sapiens (Human); CVCL_D324
• In Vitro Model: SNK-1; Peripheral blood; Homo sapiens (Human); CVCL_A671
• In Vitro Model: SNT-8 cells; Blood; Homo sapiens (Human); CVCL_A677
• Experiment for Molecule Alteration: Overexpression assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: c-Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T-cell lymphoma.

Dapt (Gsi IX)

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-223 [11]

• Resistant Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dapt (Gsi IX)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/NF-kB signaling pathway; Regulation; hsa04330
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: DND41 cells; Pleural effusion; Homo sapiens (Human); CVCL_2022
• In Vitro Model: Jurkat IkkGamma -/- cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Molt3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0624
• In Vitro Model: TALL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1736
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue staining; MTT assay; Promega assay
• Mechanism Description: Specific inhibition of miR-223 restores GSI sensitivity in GSI-resistant Molt3 cells carrying wt FBXW7. Therefore, upregulation of FBXW7 through the specific inhibition of miR-223 could offer an attractive targeted therapy for GSI-resistant T-ALLs harboring wt FBXW7 and overexpressing miR-223.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [11]

• Resistant Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dapt (Gsi IX)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/NF-kB signaling pathway; Regulation; hsa04330
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: DND41 cells; Pleural effusion; Homo sapiens (Human); CVCL_2022
• In Vitro Model: Jurkat IkkGamma -/- cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Molt3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0624
• In Vitro Model: TALL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1736
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue staining; MTT assay; Promega assay
• Mechanism Description: Specific inhibition of miR-223 restores GSI sensitivity in GSI-resistant Molt3 cells carrying wt FBXW7. Therefore, upregulation of FBXW7 through the specific inhibition of miR-223 could offer an attractive targeted therapy for GSI-resistant T-ALLs harboring wt FBXW7 and overexpressing miR-223.

MK1775

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Wee1-like protein kinase (WEE1) [12]

• Sensitive Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: MK1775
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: DND41 cells; Pleural effusion; Homo sapiens (Human); CVCL_2022
• In Vitro Model: HPB-ALL cells; Peripheral blood; Homo sapiens (Human); CVCL_1820
• In Vitro Model: CUTLL1 cells; Pleural effusion; Homo sapiens (Human); CVCL_4966
• In Vitro Model: KOPTK1 cells; N.A.; Homo sapiens (Human); CVCL_4965
• In Vivo Model: NOD-Prkdcscid IL2Rgamma null NPG mice model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: WEE1 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to glutaminolysis inhibition.Elevated WEE1 expression driven by MYC poses the possibility that T-ALL cells may be particularly dependent on WEE1 for cell proliferation and survival. Indeed, a selective WEE1 inhibitor MK1775 as a single agent reduced cell viability in a dose-dependent manner in seven T-ALL cell lines, whereas the effect on normal BM cells was minimal.

References

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• Ref 3: m6A methyltransferase Wilms' tumor 1-associated protein facilitates cell proliferation and cisplatin resistance in NK/T cell lymphoma by regulating dual-specificity phosphatases 6 expression via m6A RNA methylation .IUBMB Life. 2021 Jan;73(1):108-117. doi: 10.1002/iub.2410. Epub 2020 Nov 17. 10.1002/iub.2410
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• Ref 9: FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitorsJ Exp Med. 2007 Aug 6;204(8):1813-24. doi: 10.1084/jem.20070876. Epub 2007 Jul 23.
• Ref 10: c-Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T-cell lymphomaJ Cell Biochem. 2019 Aug;120(8):12628-12637. doi: 10.1002/jcb.28529. Epub 2019 Mar 1.
• Ref 11: Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia. 2014 Dec;28(12):2324-35. doi: 10.1038/leu.2014.133. Epub 2014 Apr 14.
• Ref 12: WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia .Haematologica. 2021 Jul 1;106(7):1816-1827. doi: 10.3324/haematol.2019.231126. 10.3324/haematol.2019.231126