Predict the therapeutic effect of HDAC inhibitor panobinostat on leukemia by global gene expression...
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A SILICA VIEW OF PANOBINOSTAT’S EFFECT ON LEUKEMIA Ying Liu & Xuan Zhu
Final Project: Computational Methods in Health Informatics (HINF 5008)
July, 2014
LEUKEMIA
• Cancer of the blood cells • Bone marrow makes abnormal white blood cells • Leukemia cells divide continuously • Most common cancer in children; more often in old adults
Four main types of leukemia • Acute myelocytic leukemia – AML • Acute lymphocytic leukemia – ALL • Chronic myelocytic leukemia – CML • Chronic lymphocytic leukemia – CLL
PANOBINOSTAT (LBH589)
• Developed by Novartis for the treatment of various cancers
• A non-selective histone deacetylase inhibitor (HDAC inhibitor)
• Clinical trials: • Myelofibrosis (exploratory) • AML (I/II) • MDS (I/II) • multiple myeloma (III) • AIDS (I/II)
DeWoskin VA & Million RP,2013
RESEARCH AIMS
To evaluate the effect of panobinostat on ALL and AML by gene expression profile analysis
DATASETS
• Downloaded from Gene Expression Omnibus (GEO) database
• Microarray data from Affymetrix Human Gene 1.0 ST Array platform (32,321 probes)
Accession number
Citation Number of records
Brief description
GSE26790 Vilas-Zornoza A, et al. Leukemia 2012.
12 Gene expression profiles before and after
panobinostat treatment in ALL cells
GSE48558 Cramer-Morales K, et al. Blood 2013.
170 Gene expression profiles in AML and ALL patient
and cell-line samples
METHODS
Microarray pre-processing: 32,321 probes
affy: Robust Multi-array Average (RMA)
Filter: 13,259 probes
Remove probes (1) IQR < 1/5 global IQR; (2) ANOVA
Select differential expression probes
limma: moderated t-statistic (Patient – Normal; Treat – No Treat) adj.P.Val < 0.05 & |logFC| > 1
OPPOSITE GENE EXPRESSION CHANGE IN PATIENT AND DRUG TREATMENT
Selected probes Patient (GSE48558): 5061/13259 probes
Heatmap logFC: fold expression change (log2)
Panobinostat (GSE26790)
Patient AML (18) B-ALL (27) T-ALL (13)
Normal Monocyte (6) B cell (11) T cell (17)
Signature 2612 2300 2440
Treat B-ALL (3) T-ALL (3)
No Treat B-ALL (3) T-ALL (3)
AML B-ALL T-ALL
Patient
B-ALL T-ALL
Panobinostat
log
FC
2
-2
METHODS
Microarray pre-processing: 32,321 probes
affy: Robust Multi-array Average (RMA)
Filter: 13,259 probes
Remove probes (1) IQR < 1/5 global IQR; (2) ANOVA
Select differential expression probes
limma: moderated t-statistic (Patient – Normal; Treat – No Treat) adj.P.Val < 0.05 & |logFC| > 1
Drug effect estimated by sum of logFC
Probe Patient Drug Drug Effect
A 5 -4 1
B -3 2 -1
B-ALL T-ALL
Panobinostat
B-ALL T-ALL
AML
BALLp TALLp
AMLp.B 0
631
431
59
372
94
66
21
AML B-ALL T-ALL
Patient
Probes with reverse expression in panobinostat treatment
Tumor (Leukemia) Inducer
ZAK (8046461) ETV6/TEL (7953981) RUNX1 (8070194) PLK1 (7994109) MYB (8122202) ZNF367 (8162601) CDK4 (7964522)
A B T B T
Patient Drug
CBX7 (8076185) NR4A2 (8055952)
Tumor Suppressor
A B T B T
Patient Drug
PANOBINOSTAT EFFECT ON LEUKEMIA SIGNATURE GENE EXPRESSION
log
FC
2
-2
105
05
10
Fold
Exp
ress
ion
Cha
nge
(log2
)
PANOBINOSTAT CORRECT ABNORMAL GENE EXPRESSION IN DIFFERENT TYPES OF LEUKEMIA
AML
Patient
B-ALL
Patient
T-ALL
Patient
Median 1.10 0.58 -1.01 0.03 1.16 1.06 SD 1.80 1.73 1.98 2.01 1.74 1.78
105
05
10
Fold
Exp
ress
ion
Cha
nge
(log2
)
105
05
10
Patient + Pan
Patient + Pan
Patient + Pan
Patient Patient Patient
p-value=0.095 p-value=0.024 p-value=1.22e-14
ANTI-LEUKEMIC EFFECT OF PANOBINOSTAT IN A MOUSE MODEL OF HUMAN ALL
Vilas-Zornoza A, Pro´sper F, Leukemia (2012)
B-ALL
T-ALL
CONCLUSION AND FUTURE DIRECTION
Panobinostat partially reversed gene expression change in leukemia
Identification of genes potentially regulated by panobinostat
Applications: • Study molecular mechanisms of panobinostat • Predict diseases that may be treated by
panobinostat
Develop a systematic quantitative approach