Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRDW8YO)

• DOT Name: Zinc finger protein Gfi-1b (GFI1B)
• Synonyms: Growth factor independent protein 1B; Potential regulator of CDKN1A translocated in CML
• Gene Name: GFI1B
• Related Disease:
  Platelet-type bleeding disorder 17
  Acute erythroid leukemia
  Acute lymphocytic leukaemia
  Acute megakaryoblastic leukemia
  Acute monocytic leukemia
  Adult teratoma
  Advanced cancer
  Arthrogryposis, renal dysfunction, and cholestasis 1
  Arthrogryposis-renal dysfunction-cholestasis syndrome
  Autoimmune thrombocytopenia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Childhood myelodysplastic syndrome
  Coagulation defect
  Idiopathic thrombocytopenic purpura
  Immune system disorder
  Immune thrombocytopenia
  leukaemia
  Leukemia
  Malignant neoplasm
  Medulloblastoma
  Myelodysplastic syndrome
  Myelofibrosis
  Myeloid leukaemia
  Teratoma
  Thrombocytopenia
  Acute myelogenous leukaemia
  Gray platelet syndrome
  Hematologic disease
  Small-cell lung cancer
  Autosomal dominant macrothrombocytopenia
  Platelet storage pool deficiency
  Lymphoma
  T-cell lymphoma
• UniProt ID: GFI1B_HUMAN
• Pfam ID: PF00096
• Sequence:
  MPRSFLVKSKKAHTYHQPRVQEDEPLWPPALTPVPRDQAPSNSPVLSTLFPNQCLDWTNL
  KREPELEQDQNLARMAPAPEGPIVLSRPQDGDSPLSDSPPFYKPSFSWDTLATTYGHSYR
  QAPSTMQSAFLEHSVSLYGSPLVPSTEPALDFSLRYSPGMDAYHCVKCNKVFSTPHGLEV
  HVRRSHSGTRPFACDICGKTFGHAVSLEQHTHVHSQERSFECRMCGKAFKRSSTLSTHLL
  IHSDTRPYPCQFCGKRFHQKSDMKKHTYIHTGEKPHKCQVCGKAFSQSSNLITHSRKHTG
  FKPFSCELCTKGFQRKVDLRRHRESQHNLK
• Function: Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages. Component of a RCOR-GFI-KDM1A-HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation. Transcriptional repressor or activator depending on both promoter and cell type context; represses promoter activity of SOCS1 and SOCS3 and thus, may regulate cytokine signaling pathways. Cooperates with GATA1 to repress target gene transcription, such as the apoptosis regulator BCL2L1; GFI1B silencing in leukemic cell lines markedly increase apoptosis rate. Inhibits down-regulation of MYC and MYB as well as the cyclin-dependent kinase inhibitor CDKN1A/P21WAF1 in IL6-treated myelomonocytic cells. Represses expression of GATA3 in T-cell lymphomas and inhibits GATA1-mediated transcription; as GATA1 also mediates erythroid GFI1B transcription, both GATA1 and GFI1B participate in a feedback regulatory pathway controlling the expression of GFI1B gene in erythroid cells. Suppresses GATA1-mediated stimulation of GFI1B promoter through protein interaction. Binds to gamma-satellite DNA and to its own promoter, auto-repressing its own expression. Alters histone methylation by recruiting histone methyltransferase to target genes promoters. Plays a role in heterochromatin formation.
• Tissue Specificity: Expressed in bone marrow and fetal liver, but also detectable in fetal spleen, fetal thymus, and testes. Detected in hematopoietic stem cells, erythroblasts, and megakaryocytes. Overexpressed in bone marrow of patients with erythroleukemia and megakaryocytic leukemia as well as in their corresponding leukemic cell lines, and markedly repressed in severe aplastic anemia (SAA).

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Platelet-type bleeding disorder 17	DISHTE4E	Definitive	Autosomal dominant	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Altered Expression	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[4]
Adult teratoma	DISBY81U	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Arthrogryposis, renal dysfunction, and cholestasis 1	DISRS2RG	Strong	Biomarker	[6]
Arthrogryposis-renal dysfunction-cholestasis syndrome	DISRQJH4	Strong	Biomarker	[6]
Autoimmune thrombocytopenia	DISNF0OI	Strong	Genetic Variation	[7]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Altered Expression	[8]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[9]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[10]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Genetic Variation	[7]
Immune system disorder	DISAEGPH	Strong	Biomarker	[11]
Immune thrombocytopenia	DISVCBNS	Strong	Genetic Variation	[7]
leukaemia	DISS7D1V	Strong	Genetic Variation	[12]
Leukemia	DISNAKFL	Strong	Genetic Variation	[12]
Malignant neoplasm	DISS6SNG	Strong	Biomarker	[13]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[13]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[9]
Myelofibrosis	DISIMP21	Strong	Altered Expression	[3]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[4]
Teratoma	DIS6ICY4	Strong	Altered Expression	[5]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[14]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[9]
Gray platelet syndrome	DISLOTCW	moderate	Biomarker	[15]
Hematologic disease	DIS9XD9A	moderate	Genetic Variation	[16]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[17]
Autosomal dominant macrothrombocytopenia	DISUTMSW	Supportive	Autosomal dominant	[18]
Platelet storage pool deficiency	DISHODOH	Supportive	Autosomal dominant	[19]
Lymphoma	DISN6V4S	Limited	Altered Expression	[20]
T-cell lymphoma	DISSXRTQ	Limited	Biomarker	[20]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Zinc finger protein Gfi-1b (GFI1B) decreases the response to substance of Doxorubicin.	[24]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger protein Gfi-1b (GFI1B).	[21]
Pomalidomide	DMTGBAX	Approved	Pomalidomide decreases the expression of Zinc finger protein Gfi-1b (GFI1B).	[22]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc finger protein Gfi-1b (GFI1B).	[23]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex.Mol Cell Biol. 2019 Jun 13;39(13):e00020-19. doi: 10.1128/MCB.00020-19. Print 2019 Jul 1.
• [3] Growth factor-independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate.Br J Haematol. 2007 Jan;136(2):212-9. doi: 10.1111/j.1365-2141.2006.06407.x. Epub 2006 Dec 8.
• [4] Growth factor independent 1b (Gfi1b) and a new splice variant of Gfi1b are highly expressed in patients with acute and chronic leukemia.Int J Hematol. 2009 May;89(4):422-430. doi: 10.1007/s12185-009-0286-5. Epub 2009 Apr 10.
• [5] InVivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma.Stem Cell Reports. 2017 Oct 10;9(4):1024-1033. doi: 10.1016/j.stemcr.2017.08.010. Epub 2017 Sep 21.
• [6] Should any genetic defect affecting -granules in platelets be classified as gray platelet syndrome?.Am J Hematol. 2016 Jul;91(7):714-8. doi: 10.1002/ajh.24359. Epub 2016 Apr 26.
• [7] Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia.Pediatr Blood Cancer. 2019 Sep;66(9):e27874. doi: 10.1002/pbc.27874. Epub 2019 Jun 17.
• [8] Additive antileukemia effects by GFI1B- and BCR-ABL-specific siRNA in advanced phase chronic myeloid leukemic cells.Cancer Gene Ther. 2013 Jul;20(7):421-7. doi: 10.1038/cgt.2013.31. Epub 2013 Jun 21.
• [9] Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome.Haematologica. 2018 Apr;103(4):614-625. doi: 10.3324/haematol.2017.167288. Epub 2018 Jan 11.
• [10] Molecular mechanisms of bleeding disorderassociated GFI1B(Q287*) mutation and its affected pathways in megakaryocytes and platelets.Haematologica. 2019 Jul;104(7):1460-1472. doi: 10.3324/haematol.2018.194555. Epub 2019 Jan 17.
• [11] Transcription factor defects causing platelet disorders. Blood Rev. 2017 Jan;31(1):1-10.
• [12] A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network.Dev Biol. 2016 Mar 15;411(2):277-286. doi: 10.1016/j.ydbio.2016.02.002. Epub 2016 Feb 3.
• [13] Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Nature. 2014 Jul 24;511(7510):428-34. doi: 10.1038/nature13379. Epub 2014 Jun 22.
• [14] T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice.Neuropsychopharmacology. 2019 Jul;44(8):1505-1512. doi: 10.1038/s41386-018-0300-9. Epub 2018 Dec 22.
• [15] A dominant-negative GFI1B mutation in the gray platelet syndrome.N Engl J Med. 2014 Jan 16;370(3):245-53. doi: 10.1056/NEJMoa1308130. Epub 2013 Dec 10.
• [16] From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation.Blood. 2015 Dec 10;126(24):2561-9. doi: 10.1182/blood-2015-06-655043. Epub 2015 Oct 7.
• [17] LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B.Cancer Res. 2017 Sep 1;77(17):4652-4662. doi: 10.1158/0008-5472.CAN-16-3502. Epub 2017 Jun 30.
• [18] GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost. 2013 Nov;11(11):2039-47. doi: 10.1111/jth.12368.
• [19] Combined alpha-delta platelet storage pool deficiency is associated with mutations in GFI1B. Mol Genet Metab. 2017 Mar;120(3):288-294. doi: 10.1016/j.ymgme.2016.12.006. Epub 2016 Dec 18.
• [20] Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas.Blood. 2007 May 15;109(10):4406-14. doi: 10.1182/blood-2006-08-043331. Epub 2007 Feb 1.
• [21] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [22] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.