Clarifying the molecular mechanism associated with carfilzomib resistance in human multiple myeloma using microarray gene expression profile and genetic interaction network

Figures & data

Figure 1 SAM plot result output of the gene expression profiling of the microarray dataset from GSE69078.

Note: In this plot, red and green dots represent the gene sets that were up- and downregulated, respectively.
Abbreviation: SAM, Significance Analysis of Microarray.

Figure 2 Heatmap visualization of the differently expressed genes identified by SAM in carfilzomib-resistant KMS-11 (GSM1692587, GSM1692588 and GSM1692589) versus parental human myeloma cell line (GSM1692593, GSM1692594 and GSM1692595).

Note: In this picture, red represents upregulated genes, while green represents downregulated genes.
Abbreviation: SAM, Significance Analysis of Microarray.

Table 1 Significant genes identified by SAM in carfilzomib-resistant KMS-11 versus parental human myeloma cell line

Gene ID	Gene name	Fold change	Gene regulation
202201_at	BLVRB	3.652113	Up
219332_at	MICALL2	2.988681	Up
208792_s_at	CLU	2.831521	Up
208791_at	CLU	2.87382	Up
205943_at	TDO2	2.881487	Up
235343_at	VASH2	2.793228	Up
207469_s_at	PIR	2.619397	Up
205081_at	CRIP1	2.318266	Up
244407_at	CYP39A1	2.900208	Up
206140_at	LHX2	2.505247	Up
205348_s_at	DYNC1I1	2.19834	Up
211458_s_at	GABARAPL1	2.346701	Up
223464_at	OSBPL5	2.171483	Up
206435_at	B4GALNT1	2.188087	Up
226884_at	LRRN1	2.112008	Up
227307_at	TSPAN18	2.121718	Up
219740_at	VASH2	2.261368	Up
223633_s_at	BC005081	2.245276	Up
208869_s_at	GABARAPL1	2.316713	Up
203729_at	EMP3	2.063944	Up
217728_at	S100A6	2.149586	Up
232549_at	RBM11	2.141973	Up
219489_s_at	NXN	2.168232	Up
222742_s_at	IFT22	2.030835	Up
214453_s_at	IFI44	2.126185	Up
223434_at	GBP3	2.010582	Up
220432_s_at	CYP39A1	2.042243	Up
202983_at	HLTF	0.24513	Down
204273_at	EDNRB	0.261948	Down
228167_at	KLHL6	0.301736	Down
213478_at	KAZN	0.367101	Down
231202_at	ALDH1L2	0.318751	Down
209723_at	SERPINB9	0.293765	Down
204271_s_at	EDNRB	0.359747	Down
206701_x_at	EDNRB	0.320717	Down
205549_at	PCP4	0.398058	Down
210644_s_at	LAIR1	0.395248	Down
47069_at	PRR5	0.447339	Down
229830_at	Unknown	0.35393	Down
205402_x_at	PRSS2	0.44509	Down
215071_s_at	HIST1H2AC	0.455068	Down
219259_at	SEMA4A	0.412331	Down
213725_x_at	XYLT1	0.444801	Down
205016_at	TGFA	0.447057	Down
219168_s_at	PRR5	0.444994	Down
206691_s_at	PDIA2	0.466426	Down
205822_s_at	HMGCS1	0.411619	Down
219255_x_at	IL17RB	0.456308	Down
205506_at	VIL1	0.472652	Down
212816_s_at	CBS	0.459518	Down
218280_x_at	HIST2H2AA3	0.499175	Down
236451_at	LOC100996579	0.431235	Down
225502_at	DOCK8	0.456397	Down
220565_at	CCR10	0.470778	Down
228821_at	ST6GAL2	0.394775	Down
214455_at	HIST1H2BC	0.487997	Down
205463_s_at	PDGFA	0.469407	Down
205898_at	CX3CR1	0.433747	Down
209598_at	PNMA2	0.454474	Down
216470_x_at	PRSS2	0.46771	Down
224156_x_at	IL17RB	0.498466	Down
208962_s_at	FADS1	0.484027	Down
225846_at	ESRP1	0.482879	Down

Abbreviation: SAM, Significant Analysis of Microarray.

Figure 3 Genetic interaction network associated with carfilzomib resistance in multiple myeloma based on String platform. In this picture, each circle represents a gene (node) and each connection represents a direct or indirect connection (edge).

Note: Line color indicates the type of interaction evidence and line thickness indicates the strength of data support.

Table 2 Molecular function analysis of the genetic interaction network associated with carfilzomib resistance in KMS-11 cell line in terms of GO

GO ID	Molecular function	Observed gene count	FDR
GO.0003988	Acetyl-CoA C-acyltransferase activity	5	6.20E-08
GO.0005515	Protein binding	42	0.00197
GO.0046983	Protein dimerization activity	14	0.00466
GO.0042802	Identical protein binding	16	0.0063
GO.0005102	Receptor binding	17	0.0073
GO.0048407	Platelet-derived growth factor binding	3	0.0107
GO.0005161	Platelet-derived growth factor receptor binding	3	0.0124
GO.0003774	Motor activity	6	0.0164
GO.0042803	Protein homodimerization activity	11	0.0202
GO.0003985	Acetyl-CoA C-acetyltransferase activity	2	0.0243
GO.0005017	Platelet-derived growth factor-activated receptor activity	2	0.0243
GO.0003824	Catalytic activity	41	0.0257
GO.0005125	Cytokine activity	6	0.0257
GO.0016740	Transferase activity	22	0.0264
GO.0019899	Enzyme binding	17	0.0298
GO.0038085	Vascular endothelial growth factor binding	2	0.0322
GO.0004714	Transmembrane receptor protein tyrosine kinase activity	4	0.049

Abbreviations: FDR, false discovery rate; GO, Gene Ontology.

Table 3 Biological process analysis of the genetic interaction network associated with carfilzomib resistance in KMS-11 cell line in terms of GO

GO ID	Biological process	Observed gene count	FDR
GO.0009605	Response to external stimulus	38	3.22E-12
GO.0002376	Immune system process	34	1.27E-08
GO.0006955	Immune response	26	3.71E-07
GO.0009991	Response to extracellular stimulus	16	8.57E-07
GO.0009628	Response to abiotic stimulus	23	1.42E-06
GO.0060548	Negative regulation of cell death	21	1.42E-06
GO.0031667	Response to nutrient levels	15	1.79E-06
GO.0006950	Response to stress	40	2.12E-06
GO.0051716	Cellular response to stimulus	54	2.41E-06
GO.0007173	Epidermal growth factor receptor signaling pathway	11	5.14E-06
GO.0010941	Regulation of cell death	25	5.37E-06
GO.0043066	Negative regulation of apoptotic process	19	6.83E-06
GO.0000422	Mitophagy	6	1.42E-05
GO.0001934	Positive regulation of protein phosphorylation	18	1.42E-05
GO.0008284	Positive regulation of cell proliferation	18	1.42E-05
GO.0033554	Cellular response to stress	25	2.09E-05
GO.0042981	Regulation of apoptotic process	23	2.09E-05
GO.0044710	Single-organism metabolic process	42	2.09E-05
GO.0050896	Response to stimulus	56	2.38E-05
GO.0016236	Macroautophagy	7	3.06E-05
GO.0043410	Positive regulation of MAPK cascade	13	3.62E-05
GO.0016049	Cell growth	8	3.78E-05
GO.0044712	Single-organism catabolic process	18	3.78E-05
GO.0031668	Cellular response to extracellular stimulus	10	4.04E-05
GO.0030334	Regulation of cell migration	15	4.43E-05
GO.0044804	Nucleophagy	5	4.43E-05

Abbreviations: FDR, false discovery rate; GO, Gene Ontology; MAPK, mitogen-activated protein kinase.

Table 4 Signaling pathway analysis of the genetic interaction network associated with carfilzomib resistance in KMS-11 cell line in terms of GO

Pathway ID	Signaling pathway	Observed gene count	FDR
4060	Cytokine–cytokine receptor interaction	13	1.28E-07
4140	Regulation of autophagy	6	4.82E-06
280	Valine, leucine and isoleucine degradation	6	6.81E-06
1212	Fatty acid metabolism	6	8.74E-06
5215	Prostate cancer	7	1.12E-05
5214	Glioma	6	2.51E-05
71	Fatty acid degradation	5	8.59E-05
900	Terpenoid backbone biosynthesis	4	0.000108
72	Synthesis and degradation of ketone bodies	3	0.000297
270	Cysteine and methionine metabolism	4	0.000733
5200	Pathways in cancer	9	0.000733
1100	Metabolic pathways	17	0.00106
4962	Vasopressin-regulated water reabsorption	4	0.00139
5206	MicroRNAs in cancer	6	0.0015
5212	Pancreatic cancer	4	0.00433
650	Butanoate metabolism	3	0.00487
5218	Melanoma	4	0.00615
4012	ErbB signaling pathway	4	0.0111
4540	Gap junction	4	0.0111

Abbreviations: FDR, false discovery rate; GO, Gene Ontology.