Disease Information

General Information of the Disease (ID: DIS00055)

• Name: Chronic lymphocytic leukemia
• ICD: ICD-11: 2A82

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Bendamustine hydrochloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Bendamustine hydrochloride
• 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.

Fludarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 17p13 (Unclear) [2]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Fludarabine
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [3]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.

Key Molecule: hsa-mir-221 [3]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protocadherin Fat 1 (FAT1) [4]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: White blood cell count assay
• Mechanism Description: FAT1 and its mutational inactivation have been linked to activation of the WNT pathway in solid tumors and to chemoresistance in chronic lymphocytic leukemia and could serve as an attractive therapeutic target.

Key Molecule: Cellular tumor antigen p53 (TP53) [5]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.

Key Molecule: Serine-protein kinase ATM (ATM) [5]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [6]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: hsa-mir-181 [6]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [6]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [6]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [6]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fludarabine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase BTK (BTK) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.C481R
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.C481S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [8]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.C481S
• Resistant Drug: Ibrutinib
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.S707Y
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.P664W
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.P664S
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.L845F
• Resistant Drug: Ibrutinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [8]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; p.R665W+p.L845F+p.S707Y
• Resistant Drug: Ibrutinib
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: In contrast to the BTKC481S mutation, which causes eventual loss of BTK inhibition by ibrutinib, PLCG2 mutations are all potentially gain-of-function mutations. Situated downstream from BTK, PLCG2 mutations allow for continued signalling regardless of BTK activity. After stimulation with anti-IgM antibody, cells with either the PLCG2R665W or PLCG2L845F mutations were found to have sustained BCR signalling that was not inhibited by ibrutinib, as measured by calcium-flux assays and phosphorylation of ERK and AKT.

Rituximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 17p13 (Unclear) [2]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Rituximab
• 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) [9]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Rituximab
• 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) [1]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Rituximab
• 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.

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [10]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Missense mutation; p.G101V (c.302G>T)
• Resistant Drug: Venetoclax
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KMS-12-PE cells; Pleural effusion; Homo sapiens (Human); CVCL_1333
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

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

Purine analogues

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Purine analogues
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: karyotyping assay
• Mechanism Description: TP53 abnormalities lead to resistance to purine a.logues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL).

References

• Ref 1: 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.
• Ref 2: Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007 Sep;92(9):1242-5. doi: 10.3324/haematol.10720. Epub 2007 Aug 1.
• Ref 3: Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia. Mol Cancer. 2010 May 20;9:115. doi: 10.1186/1476-4598-9-115.
• Ref 4: Mutational spectrum of adult T-ALL. Oncotarget. 2015 Feb 20;6(5):2754-66. doi: 10.18632/oncotarget.2218.
• Ref 5: FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.
• Ref 6: miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Carcinogenesis. 2012 Jul;33(7):1294-301. doi: 10.1093/carcin/bgs179. Epub 2012 May 18.
• Ref 7: Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
• Ref 8: Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427
• Ref 9: The mutational signature of chronic lymphocytic leukemia. Biochem J. 2016 Nov 1;473(21):3725-3740. doi: 10.1042/BCJ20160256.
• Ref 10: Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutationsNat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1.
• Ref 11: TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes. Int J Cancer. 2016 Oct 15;139(8):1759-63. doi: 10.1002/ijc.30222. Epub 2016 Jun 24.