Genomic and transcriptomic landscapes of acute promyelocy3c leukemia - - PowerPoint PPT Presentation

▶
genomic and transcriptomic landscapes of acute
SMART_READER_LITE
LIVE PREVIEW

Genomic and transcriptomic landscapes of acute promyelocy3c leukemia - - PowerPoint PPT Presentation

Aug 19, 2022 300 likes •574 views

Genomic and transcriptomic landscapes of acute promyelocy3c leukemia Kankan Wang State Key Laboratory of Medical Genomics Rui-Jin Hospital Shanghai Jiaotong University School of Medicine Understanding the pathogenesis and treatment of APL

slide-1
SLIDE 1

Genomic and transcriptomic landscapes of acute promyelocy3c leukemia

Kankan Wang State Key Laboratory of Medical Genomics Rui-Jin Hospital Shanghai Jiaotong University School of Medicine

slide-2
SLIDE 2

Understanding the pathogenesis and treatment of APL using high-throughput technologies

CH3 RNA polymerase

ChIP-seq RNA-seq

PML/RARα APL Effects of ATRA and ATO (co-regulators)

? ?

slide-3
SLIDE 3

Hallmarks of acute promyelocy3c leukemia

How does PML/RARα drive the development of APL?

slide-4
SLIDE 4
  • PML/RARα retains the DNA binding

domain of wild-type RARα.

  • PML/RARα acts as a strong

transcriptional repressor.

  • Myeloid commitment is hardly affected

in various RAR-deficient mice.

Genome-wide PML/RARα binding sites

ChIP-chip/ChIP-seq

slide-5
SLIDE 5

Wang et al. Cancer Cell 2010 Martens et al. Cancer Cell 2010

Genome-wide binding pictures of PML/RARα

ATRA ATRA PU.1-mediated transactivation was restored Genes repressed by PML/RARα were reactivated Increased in H3K9K14 acetylation Induced transcriptional changes correlate with H3K9K14 acetylation

slide-6
SLIDE 6

PU.1 and RARE half sites are the most significant mo3fs in the PML/RARα ChIP regions

Wang et al. Cancer Cell 2010

slide-7
SLIDE 7

Wang et al. Cancer Cell 2010

Recruitment of PML/RARα to chromaEn pre-bound by PU.1

PML/RARα predominantly represses PU.1-regulated genes

Repression of PU.1-dependent transacEvaEon through both PU.1 and RARE half sites

slide-8
SLIDE 8

PML/RARα tends to colocalize with RXR preferen3ally on promoter regions

Martens et al. Cancer Cell 2010

slide-9
SLIDE 9

ATRA treatment increases the level of H3K9K14ac but not H3K9me3 and H3K27me3

Martens et al. Cancer Cell 2010

slide-10
SLIDE 10

PML/ RARα PML/ RARα HCK PMSB8 Tissue factor

PU.1 PU.1

PMSB9 PMSB10 PML/ RARα PU.1

PU.1 PU.1

POL II

Detailed analysis of key targets Genome-wide PML/RARα binding

PML/ RARα CDKN2D Indirect binding Binding to multiple PU.1 Coordinated regulation Binding to ER8 Hemorrhage Yan JS, et al,

  • PNAS. 2010

Antigen presentation Yang XW, et al,

  • Oncogene. 2014

Differentiation & Cell cycle Wang YW, et al, Cell Death Dis. 2014 Tumor suppression Zou DD, et al, Leukemia Res. 2010

Regulatory features and func3ons of PML/RARα key targets in APL

ER8

slide-11
SLIDE 11

PML/RARα transac3vates the 3ssue factor promoter through an indirect interac3on

Yan et al. PNAS 2010

slide-12
SLIDE 12

PML/RARα exerted both repressive and ac3va3ng func3ons

Unpublished data

slide-13
SLIDE 13

Func3onally importance of both PML/RARα-repressed and -ac3vated targets

Unpublished data

slide-14
SLIDE 14

Repression was associated with RARα, whereas ac3va3on was independent of RARα

Unpublished data

slide-15
SLIDE 15

Dis3nct ATRA effects on PML/RARα-ac3vated and -repressed genes

Unpublished data

slide-16
SLIDE 16

PML/RARα preferen3ally existed within super-enhancer regions

Unpublished data

slide-17
SLIDE 17

Transcriptome analysis of the mechanism of ATRA action

  • RNA-seq/microarray
  • Ribo-minus RNA-seq
slide-18
SLIDE 18

M M

12 h 48 h 12 h 48 h 12 h 48 h

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

M M M M

12 h 48 h 12 h 48 h 12 h 48 h

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

2 1

  • 1
  • 2

M M

ATRA regulates gene expression at the transcriptomic level, whereas ATO func3ons at the proteomic level

Transcriptome Proteome

Zheng et al. PNAS 2005

slide-19
SLIDE 19

Molecular networks underlying the combina3on of ATRA and ATO in NB4 cells

CD44 SELL CD11b CD18 ICAM1

Surface Molecules Restoration of NB Plasma Membrane Cytoplasm

IFNAR2 JAK1 TYK2 ISGF3G STAT1 STAT2 IFNGR JAK1 JAK2 STAT1 IRF7 ISGF3 STAT1

IFN Pathway

G-CSF-R Receptor GRB2 SOS2 Ras Raf MAPK6 Receptor TRAF2 Daxx ASK1 MKK3 Rac P38 MKK4/7 JNK2 PTPN9 MEK1

MAPK-JNK-p38 Pathway

G-CSF-R SHP2

TFs/CoFs

MEKK1

Protein Synthesis PML-RARα Degradation Cell Cycle Nucleus

TRADD FADD CASP10 CASP8 CASP3 CASP7 cytc APAF1 CASP9 BCL2 Mitochondria Apoptosis

Apoptosis

IRF1 CASP1 TRAIL-R FADD PDCD6IP BCL2A1 TNF-R STK24 BAK1

M

CDK4 CCND2 CDK2 CCNE1 CDK2 CCNA2 CDK7 CCNH CDK1 CCNA2 CDK1 CCNB1 CDKN2D CDKN1A CDC25B CHEK1 PCNA GADD45B CDC25A

G1 G2 S

CDKN1B

Stress Cytoskeleton

AHSA1 HSPCA DNAJA1 HSPA8 DNAJB1 Receptor G protein AC ATP cAMP PKA

cAMP-PKA Pathway

AKAP13 AKAP1 PDE4DIP AKAP9 Receptor G protein PLCB PIP2 IP3 DG2 ITPR RYR3 Ca2+ CALM Ca2+ PKC

Calcium Pathway

PKA ANK3

ER

NUCB2 AKAP9 S100A8 S100A9 PLSCR1 CGREF1 SP100 SP110 SP140 PSME2 PML

  • thers

PML-RARα P/CAF NCOA3 TIF CBP

RA RA Pathway

EP300 ID1 BHLHB2 ID2 CEBPZ CEBPB CEBPG CEBPD CEBPE HHEX

TFs/CoFs

40S AUG

Proteins

EIF4A1 EEF1B2 EEF1A1 EEF1D EEF1G 60S EIF4B EIF4G1 80S PML-RARα SUMO1 UBE2L6 UBE1L UBE4B UBE3C PSMB9 PSMB8 PSMB10 PSMC3 PSMD13 PSMC2 Sumoylated PML-RARα SENP5 MAP2 MYH3 MYOM1 FBN2 Ubiquitiated PML-RARα Degradation of PML-RARα proteasome

Cell Cycle Arrest

IFI16b GAS7 ARHI PEG10 CCNG2 PIBF1 SELPLG CD44 SELL CD11b CD18 ICAM1

Surface Molecules Restoration of NB Plasma Membrane Cytoplasm

IFNAR2 JAK1 TYK2 ISGF3G STAT1 STAT2 IFNGR JAK1 JAK2 STAT1 IRF7 ISGF3 STAT1

IFN Pathway

G-CSF-R Receptor GRB2 SOS2 Ras Raf MAPK6 Receptor TRAF2 Daxx ASK1 MKK3 Rac P38 MKK4/7 JNK2 PTPN9 MEK1

MAPK-JNK-p38 Pathway

G-CSF-R SHP2

TFs/CoFs

MEKK1

Protein Synthesis PML-RARα Degradation Cell Cycle Nucleus

TRADD FADD CASP10 CASP8 CASP3 CASP7 cytc APAF1 CASP9 BCL2 Mitochondria Apoptosis

Apoptosis

IRF1 CASP1 TRAIL-R FADD PDCD6IP BCL2A1 TNF-R STK24 BAK1

M

CDK4 CCND2 CDK2 CCNE1 CDK2 CCNA2 CDK7 CCNH CDK1 CCNA2 CDK1 CCNB1 CDKN2D CDKN1A CDC25B CHEK1 PCNA GADD45B CDC25A

G1 G2 S

CDKN1B

Stress Cytoskeleton

AHSA1 HSPCA DNAJA1 HSPA8 DNAJB1 AHSA1 HSPCA DNAJA1 HSPA8 DNAJB1 Receptor G protein AC ATP cAMP PKA

cAMP-PKA Pathway

AKAP13 AKAP1 PDE4DIP AKAP9 Receptor G protein PLCB PIP2 IP3 DG2 ITPR RYR3 Ca2+ CALM Ca2+ PKC

Calcium Pathway

PKA ANK3

ER

NUCB2 AKAP9 S100A8 S100A9 PLSCR1 CGREF1 S100A8 S100A9 PLSCR1 CGREF1 SP100 SP110 SP140 PSME2 PML

  • thers

SP100 SP110 SP140 PSME2 PML

  • thers

PML-RARα P/CAF NCOA3 TIF CBP

RA RA Pathway

EP300 ID1 BHLHB2 ID2 CEBPZ CEBPB CEBPG CEBPD CEBPE HHEX

TFs/CoFs

40S AUG AUG

Proteins

EIF4A1 EEF1B2 EEF1A1 EEF1D EEF1G 60S 60S EIF4B EIF4G1 80S PML-RARα SUMO1 UBE2L6 UBE1L UBE4B UBE3C UBE2L6 UBE1L UBE4B UBE3C PSMB9 PSMB8 PSMB10 PSMC3 PSMD13 PSMC2 PSMB9 PSMB8 PSMB10 PSMC3 PSMD13 PSMC2 Sumoylated PML-RARα SENP5 MAP2 MYH3 MYOM1 FBN2 MAP2 MYH3 MYOM1 FBN2 Ubiquitiated PML-RARα Degradation of PML-RARα proteasome

Cell Cycle Arrest

IFI16b GAS7 ARHI PEG10 CCNG2 PIBF1 SELPLG

IRF1

Zheng et al. PNAS 2005

slide-20
SLIDE 20

Circular RNA genera3ng from the fusion site of PML/RARα is oncogenic and contributes to cellular transforma3on

Zepp et al. Cell 2017

slide-21
SLIDE 21

Dynamic regulated cicrRNA profiling upon ATRA treatment of APL cells

Unpublished data

slide-22
SLIDE 22

cicrRNA regula3on independent of their host linear mRNA

Unpublished data

slide-23
SLIDE 23

Unpublished data

Requirement of circ-RELL1 in ATRA-induced differen3a3on of APL cells

slide-24
SLIDE 24

Summary

Genome-wide binding pictures of PML/RARα

  • PML/RARα selectively targets PU.1-regulated genes.
  • PML/RARα is colocalized with RXR on chromatin.
  • PML/RARα exerts both activation and repression roles of in

driving APL. Regulatory features and functions of key targets of PML/ RARα. Transcriptomic view of the mechanism of ATRA action

  • ATRA induces transcriptional remodeling and a series of

signaling pathways in APL cells.

  • ATRA dynamically regulates a number of cicrRNAs upon

ATRA treatment.

slide-25
SLIDE 25

Acknowledgements

Omics platforms Yun Tan Ping Wang Yizhen Li Xuehua Zhu Functional studies Wen Jin Xianwen Yang Xuefei Ma Yewei Wang Bioinformatics analysis Hai Fang Ming Zhao Jiantao Shi Huanwei Wang