Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC...
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Transcript of Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC...
![Page 1: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/1.jpg)
Molecular Pathogenesis of Leukemia
PML/RAR
MLL translocations
PLZF/RARetc.AML1/ETO
CBF/SMMHCTEL/AML1
Other transloc.
BCR-ABL
Flt3 ITDor mutation
N/K-RASmutation
C-KIT mutation
PDGFR
Mutations that affect proliferation/survival
Type I mutationsType I mutations
Mutations that impair differentiation
Type II mutationsType II mutations
Trisomy 85q-, 7q-, 20q-
Complex Caryotypes
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Oncogene addiction of human cancers
Weinstein, Science 2002
*
* C-myc in experimental modelsBcr/abl, PML/RAR in human (?)
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Molecular Lesions Start in a Stem Molecular Lesions Start in a Stem Cell PopulationCell Population
Current Treatment approaches :Kill Cancer BulkKill Cancer Stem cells
![Page 4: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/4.jpg)
Cancer stem cells undergo limited differentiationCancer stem cells undergo limited differentiation
Therapeutic Therapeutic Approach:Approach:
Induce Cancer Stem Induce Cancer Stem Cells DifferentiationCells Differentiation
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Retinoic acid induces differentiation of APL blastsRetinoic acid induces differentiation of APL blastsExpressing PML/RARExpressing PML/RAR
1010-6-6 M M(or RA 10-9 M)
![Page 6: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/6.jpg)
Acute Promyelocytic Leukemia (APL) and the Acute Promyelocytic Leukemia (APL) and the 15;17 translocation15;17 translocation
Grignani et al, Blood 1994
![Page 7: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/7.jpg)
Oncogenic Biological Effects of PML/RAR Expression in Human Cells
Grignani et al. Cell 1993, Blood 2000
Commitment induction
PML/RAR expression
Block ofApoptosis
Self-renewal
Further mutations
XXXXX
Differentiationblock
LEUKEMIALEUKEMIA
Self-renewal
Differentiation
Commitment
Normal Hematopoiesis
Apoptosis
Biological Effects of Retinoic Acid in PML/RAR Expressing Human Cells
PML/RAR expression
Grignani et al. Cell 1993, Blood 2000
Self-renewal
Commitment induction
Differentiation
Apoptosis
RASelf-renewal
Differentiation
Commitment
Normal Hematopoiesis
Apoptosis
![Page 8: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/8.jpg)
RARE RARE
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
Dnmt1Sin3A
MeCP2
Ac AcAcAc
N-CoR
Transcriptional Repression by PML/RARTranscriptional Repression by PML/RARInvolves DNA Methyl-TransferasesInvolves DNA Methyl-Transferases
HDACHDAC
Ac Ac
Ac
Francesco Grignani
![Page 9: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/9.jpg)
HMTHMT
RARE RARE
RAR
RARE
RAR
PMLPML
RARE
Dnmt1Sin3A
MeCP2N-CoR HDACHDAC
pASepharose
DNA+Protein
Immunoprecipitationw/anti-X antibody
RARE RARE
DNA extraction
PCR
Histone Methyl-transferases participate in the PML/RAR transcriptional complex
![Page 10: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/10.jpg)
HMTHMT
RARE RARE
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
Dnmt1Sin3A
MeCP2
Ac AcAcAc
N-CoR
Transcriptional Repression by PML/RARTranscriptional Repression by PML/RAR
HDACHDAC
Ac Ac
Ac
Francesco Grignani
![Page 11: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/11.jpg)
RARE RARE
RAR
RARE
RAR
PMLPML
RARE
Ac AcAcAc
Transcriptional Repression by PML/RARTranscriptional Repression by PML/RAR
RA RA10-6 M
Francesco Grignani
CH3CH3
Dnmt1Sin3A
MeCP2N-CoR
HDAC
Ac Ac
Ac
HMTHMT
CH3CH3
Transcriptional Activation by Retinoic AcidTranscriptional Activation by Retinoic Acid
MeCP2
Sin3A
HDAC
Dnmt1
N-CoR
RAR
RARE
RAR
PMLPML
RARE
RA RA10-6 M
Ac AcAcAc
Ac AcAcAcCBP
pCAF
pCAF complex
N-CoA
PRMT1PRMT1BTG2BTG2
CH3CH3
PML/RARPML/RAR degradation by Retinoic Acid degradation by Retinoic Acid
MeCP2
Sin3A
HDAC
Dnmt1
N-CoR
RARE RARE
CBP
pCAF
pCAF complex
N-CoA
PRMT1PRMT1BTG2BTG2
![Page 12: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/12.jpg)
90-95%90-95%
3-4%3-4%
1%1%
1%1%
1%1%
APL Chromosomal Translocations Always Involve APL Chromosomal Translocations Always Involve RARRARBut not all APLs are the SameBut not all APLs are the Same
RA-sensitiveRA-sensitive
RA-resistantRA-resistant
??
??
??
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Sin3A
The AML1/ETO Fusion Protein Recruits a The AML1/ETO Fusion Protein Recruits a Repressor ComplexRepressor Complex
HDACHDAC
Ac Ac
Ac
AML1AML1 AML1AML1
ETOETOETOETON-CoRN-CoR
![Page 14: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/14.jpg)
Altered regulation of chromatin structure is common in AML
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Beyond Retinoic Acid and APLBeyond Retinoic Acid and APL
1- Some PML/RAR1- Some PML/RAR APL relapse and are ATRA resistant APL relapse and are ATRA resistant
2- PLZF/RAR2- PLZF/RAR APLs are ATRA resistant APLs are ATRA resistant
3- The AML1/ETO fusion protein of M2/4 AMLs3- The AML1/ETO fusion protein of M2/4 AMLs fuctions by recruiting a co-repressor/HDAC complexfuctions by recruiting a co-repressor/HDAC complex
4- Other leukemias are associated to altered chromatin 4- Other leukemias are associated to altered chromatin structure regulationstructure regulation
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Sin3A
N-CoR
Dnmt1
MeCP2HDAC
Ac Ac
Ac
RAR
RARE
RAR
PMLPML
RARE
AsAs22OO3 3 induces degradation of PML/RARinduces degradation of PML/RAR
CH3CH3
As
As
As
As
As
As
As
Sin3A
N-CoR
Dnmt1
MeCP2
HDAC
Ac AcAc
CH3CH3
As
As
As
As
As
As
As
AsAs22OO3 3 induces degradation of PML/RARinduces degradation of PML/RAR
![Page 17: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/17.jpg)
Riadattata da: Esteller M., J Pathol 2005
HDACinhibitors
(TSA,VPA,etc)5-azacytidine
Terapia Epigenetica
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Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I, Warrell R, Nimer S.Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-
azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia. 2006 Feb;20(2):212-7. Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H, Gattermann
N. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in
combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006 Jan 1;106(1):112-9. Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C, Germing U, Haas R, Gattermann N.Results of a
phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005 Dec;84 Suppl 13:61-6. McMullin MF, Nugent E, Thompson A, Hull D, Jones FG, Grimwade D.Prolonged molecular remission in PML-RAR-positive acute promyelocytic leukemia treated with minimal chemotherapy
followed by maintenance including the histone deacetylase inhibitor sodium valproate. Leukemia. 2005 Sep;19(9):1676-7.
HDAC inhibitors in AML and MDS treatment
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E2F
RbHDAC X
A.
B.
C.
HDAC inhibition: potential effects on cell growth
Activation of myc-target genes
Suppression of Rb activity
Increased activity of “HAT” fusion proteins
![Page 20: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/20.jpg)
HDAC inhibition: potential effects on EBV regulated pathways
HDAC inhibition may have “EBV-like” effects
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RARE RARE
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
Dnmt1Sin3A
MeCP2N-CoR
PML/RARPML/RARActivity Depends on its Activity Depends on its Corepressors Interaction InterfaceCorepressors Interaction Interface
HDAC
Ac Ac
Ac
![Page 22: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/22.jpg)
Sin3A
The AML1/The AML1/ETO Activity Depends on its Activity Depends on its Corepressors Interaction InterfaceCorepressors Interaction Interface
HDACHDAC
Ac Ac
Ac
AML1AML1 AML1AML1
ETOETOETOETON-CoR/N-CoR/SMRTSMRT
![Page 23: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/23.jpg)
Sin3A
N-CoR
CH3CH3
Dnmt1
MeCP2RAR
RARE
RAR
PMLPML
RARE
Block of N-CoR/PML-RARBlock of N-CoR/PML-RAR interactions interactions
HDAC
Ac Ac
Ac
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
![Page 24: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/24.jpg)
A/BA/B CC DD EEPMLPML FF
PML/RARPML/RAR
IDNIDN IDCIDCN-CoR/SMRTN-CoR/SMRT
RD3RD3
AML1/ETOAML1/ETO
ZnFZnFAML1AML1
Fusion Proteins / Co-Repressors Interaction DomainsFusion Proteins / Co-Repressors Interaction Domains
ETOETO
![Page 25: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/25.jpg)
Sin3A
N-CoR
CH3CH3
Dnmt1
MeCP2RAR
RARE
RAR
PMLPML
RARE
Transcriptional Repression by PML/RARTranscriptional Repression by PML/RAR
HDAC
Ac Ac
Ac
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
IDC Expression impairs N-CoR/RARIDC Expression impairs N-CoR/RAR binding binding
CH3CH3
PMLPML
RAR
RARE
RAR
RARE
Sin3A
HDAC
Dnmt1
N-CoR
MeCP2
![Page 26: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/26.jpg)
The AML1/The AML1/ETO Fusion Protein Recruits a Fusion Protein Recruits a Repressor ComplexRepressor Complex
AML1AML1 AML1AML1
ETOETOETOETO
Sin3A
HDACHDACN-CoR/N-CoR/SMRTSMRT
![Page 27: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/27.jpg)
PML/RAR-regulated AML1/ETO-regulated
Disruption of the Corepressor Complex Increases the Expression of Fusion Proteins Target Genes
NB4/ NB4R4 SKNO1
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Block of Fusion Proteins-Corepressors Interaction Block of Fusion Proteins-Corepressors Interaction Restores D3-Induced Differentiation ResponseRestores D3-Induced Differentiation Response
PML/RAR AML1/ETO
![Page 29: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/29.jpg)
NB4R4+RANB4R4+RA NB4R4-IDC+RANB4R4-IDC+RA
Block of PML/RARBlock of PML/RAR-Corepressors Interaction Restores -Corepressors Interaction Restores RA-Induced Terminal Differentiation in RA-Resistant CellsRA-Induced Terminal Differentiation in RA-Resistant Cells
![Page 30: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/30.jpg)
NBT Surface Markers Growth
Block of AML1/ETO-Corepressors Interaction Increases Block of AML1/ETO-Corepressors Interaction Increases RA-Induced Differentiation ResponseRA-Induced Differentiation Response
![Page 31: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/31.jpg)
IDC/IDN Expression Induces PML/RARIDC/IDN Expression Induces PML/RARProtein DegradationProtein Degradation
The Fusion RNA is Expressed
The Protein is Undetectable
![Page 32: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/32.jpg)
Sin3A
N-CoR
CH3CH3
Dnmt1
MeCP2RAR
RARE
RAR
PMLPML
RARE
Transcriptional Repression by PML/RARTranscriptional Repression by PML/RAR
HDAC
Ac Ac
Ac
RAR
RARE
RAR
PMLPML
RARE
CH3CH3
IDC Expression impairs N-CoR/RARIDC Expression impairs N-CoR/RAR binding binding
CH3CH3
PMLPML
RAR
RARE
RAR
RARE
Sin3A
HDAC
Dnmt1
N-CoR
MeCP2
CH3CH3
Sin3A
HDAC
Dnmt1
N-CoR
MeCP2
RARE RARE
IDC Expression induces PML/RARIDC Expression induces PML/RAR degradation degradation
![Page 33: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/33.jpg)
Protein transfer strategiesProtein transfer strategies
Protein production in bacteria
Addition to cell culture medium
Lysis and 6-H-based
purification
TATHA IDC6H
TAT6H HA IDC
6H IDC
6H IDC
6H IDC
PEP1
Coupling with “cargo peptide”
Quick urea removal
A. B.
![Page 34: Molecular Pathogenesis of Leukemia PML/RAR MLL translocations PLZF/RAR etc. AML1/ETO CBF /SMMHC TEL/AML1 Other transloc. BCR-ABL Flt3 ITD or mutation.](https://reader036.fdocuments.us/reader036/viewer/2022062421/56649c765503460f9492b3db/html5/thumbnails/34.jpg)
Vitamin D3-induced differentiation
Corepressors interaction peptides are effective when transduced via TAT-mediated protein transfer
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GSH
GST PMLRAR
35S N-CoRGSH
GSHGST PMLRAR
IDC 20-mer competes for PML/RAR binding to N-CoR in GST pull-down experiments
35 S N-C
oR
GSTGST-P
ML/R
AR
- 1:5 1:50IDC 20-mer - -
+ IDC 20-mer
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Specific peptide interference reveals BCL6 transcriptionaland oncogenic mechanisms in B-cell lymphoma cellsJose M Polo, Tania Dell’Oso, Stella Maris Ranuncolo, Leandro Cerchietti, David Beck, Gustavo F Da Silva,Gilbert G Prive, Jonathan D Licht & Ari Melnick Nature Medicine 10:1329, 2004
BTB domain peptide inhibitors may constitute a novel therapeutic agent for B-cell lymphomas.
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ConclusionsConclusions
1- The search for the best molecular target in 1- The search for the best molecular target in leukemia therapy points again at fusion proteinsleukemia therapy points again at fusion proteins
2- Fusion proteins alter epigenetic regulation of 2- Fusion proteins alter epigenetic regulation of target genes by recruiting enzymestarget genes by recruiting enzymes
3- Enzyme inhibitors are being tested in clinical 3- Enzyme inhibitors are being tested in clinical trialstrials
4- The use of blocking peptides could contribute to 4- The use of blocking peptides could contribute to neutralize oncogenic proteins neutralize oncogenic proteins
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Francesco GrignaniFrancesco Grignani
Serena Racanicchi, Serena Racanicchi, Monia Billi,Monia Billi,Maddalena PanigadaMaddalena Panigada,Chiara Maccherani,Concetta LiberatoreGiovanni Rizzo
Clara Nervi Clara Nervi
Vania GelmettiVania Gelmetti,
Patologia Generale and MISO,Dept. of Clin. and Experimental Medicine, Perugia University,Italy
Dept. of Histology and Embriology,Universita` di Roma ‘La Sapienza’, Parco Bio-Medico Scientifico San Raffaele, Roma, Italy
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0 30 60 180 0 30 60 180
5x10-8 M RA
RAR-
Actin
C+ C+
ChIP -acetyl H3 ChIP -acetyl H4
0 30 60 18015 0 30 60 18015
NB4 NB4 IDC NB4 NB4 IDC
IDC Expression Allowes Histone Acetylation on RAR Target Genes by Low RA Concentrations
RA hrs
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RAR
RARE
RXR
RARERARE RARE
Sin3A
Ac AcAcAc
N-CoR
Inactive RARInactive RAR
HDAC
Ac Ac
Ac
RA RA10-9 M
Francesco Grignani
Transcriptional Activation by Retinoic AcidTranscriptional Activation by Retinoic Acid
Sin3A
HDACN-CoR
CBP
pCAF
pCAF complex
N-CoA
RAR
RARE
RXR
RARE
RA RA10-9 M
Ac AcAcAc
Ac AcAcAc
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RARGST GSHGST PMLRAR
+
35S N-CoR
+/- RAGSH
GSH
GST PMLRAR
PML/RAR binds N-CoR with high affinity
Grignani et al. Nature 1998
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NB4-R4NB4-R4 NB4-R4-IDCNB4-R4-IDC
NB4NB4 NB4-IDCNB4-IDC
IDC-induced PML/RARIDC-induced PML/RAR degrdation reconstitute degrdation reconstitute PML-nuclear bodiesPML-nuclear bodies
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Many HDAC InhibitorsMany HDAC Inhibitorsare entering are entering clinical trialsclinical trials
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-PML Mo-Ab-PML Mo-Ab
Expression of the PML/RARExpression of the PML/RAR Fusion Protein Fusion Protein Alters PML Nuclear Bodies. RA Restores ThemAlters PML Nuclear Bodies. RA Restores Them
HL60 CellsHL60 Cells(NO PML/RAR(NO PML/RAR))
NB4 CellsNB4 Cells(PML/RAR(PML/RAR))
NB4 Cells NB4 Cells +RA 10+RA 10-6-6 M M