supplementary information immunomodulatory drugs … · ev 1 ev 1 crbn mct1 ... scr 1 3 crbn cd147...

Eichner et al.

Supplementary Information

Immunomodulatory drugs disrupt the CRBN-CD147/MCT1 axis to exert anti-tumor activity and teratogenicity

Ruth Eichner, Michael Heider*, Vanesa Fernández-Sáiz*, Frauke van Bebber, Anne-Kathrin

Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria

Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop,

Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid,

Katharina S. Götze, Bernhard Kuster and Florian Bassermann

*Equal contribution Correspondence to: [email protected]

Inventory: • Supplementary Figures 1-11 • Supplementary Table 2

Nature Medicine: doi:10.1038/nm.4128

Eichner et al.

Supplementary Figures

Supplementary Fig. 1. Purification of the CRBN complex.

(a) Tandem-Strep-single-Flag-tagged CRBN (CRBN-SF) was expressed in HEK293T

cells and subjected to a sequential immunopurification approach comprising immobilization

on Strep-Tactin beads, elution with desthiobiotin, immobilization on anti-Flag resin and

elution with 3x-Flag octapeptide. The Flag eluate was separated by SDS-PAGE and analyzed

by mass spectrometry. As controls, purifications were performed from HEK293T transfected

with an empty vector (EV) or non-tagged CRBN. The depicted silver stained gel corresponds

to 5% of the final Flag-eluates.

(b) Sequences of identified unique peptides corresponding to CD147 and MCT1. A full

list of identified CRBN interactors is shown in Supplementary Table 1.

EV! CRBN! CRBN-SF!MW

(kDa)!250!130!100!75!55!35!25!15!11!

CRBN!

a!

b!Sequence

Mascot Ion score Modifications Start Stop

(K)GGVVLKEDALPGQK(T) 88.64 58 71 (K)EDALPGQK(T) 58.06 64 71 (K)SSEHINEGETAMLVcK(S) 78.3 Carbamidomethyl (+57) 112 127 (K)SESVPPVTDWAWYK(I) 56.25 128 141 (R)FFVSSSQGR(S) 41.36 158 166 (R)SELHIENLNmEADPGQYR(C) 87.48 Oxidation (+16) 167 184 (K)GSDQAIITLR(V) 66.62 192 201 (R)RKPEDVLDDDDAGSAPLK(S) 83.3 233 250

CD147 - P35613

Sequence Mascot Ion score Modifications Start Stop

(K)SITVFFK(E) 40 39 45 (K)DLHDANTDLIGRHPK(Q) 55,97 225 239 (K)DLHDANTDLIGR(H) 81,49 225 236 (R)LNDMYGDYK(Y) 54,99 412 420 (K)KESKEEETSIDVAGKPNEVTK(A) 61,98 459 479 (K)ESKEEETSIDVAGKPNEVTK(A) 52,8 460 479

MCT1 - P53985


Eichner et al.

Supplementary Fig. 2. CRBN interacts with CD147 and MCT1 proteins to promote their

stability and mediate MM cell proliferation.

(a) Immunoprecipitation of Flag-CD147 (left) and Flag-MCT1 (right) from HEK293T

cells. Immunoprecipitates were analyzed by immunoblotting.

(b) Pull down assays of recombinant GST-CRBN and in-vitro translated and 35S-labeled

CD147 and MCT1 proteins treated with solvent or lenalidomide as indicated. Bound protein

fractions were visualized by autoradiograpy.

(c) Immunoblot analysis of MM1S cells in which CRBN expression was silenced by

a bWCE IP: anti-Flag

EV CD14

7

CRBN

CD147(anti-Flag)

CUL1

EV CD14

7

MW(kDa)

35 –

55 –

55 –

90 –

WCE IP: anti-Flag

EV MCT

1

EV MCT

1

CRBN

MCT1(anti-Flag)

CUL1

40 –

55 –

90 –

MW(kDa)

MCT1

-

CD147

100

-

-

-

7055

35

25

-

GST

GST-CRBN

Coom

asie

-100-

-

-

7055

35

25

-

MW(kDa)

[35S]

Met

Auto

-radio

grap

h

– – + + – – + + Len.

CD147MCT1

dc

sh_CRBN-2Len. - +- ++CRBN

CD147

MCT1

β-actin

-

sh_Ctrl

+ +- ---- -+ +--- -- -++

sh_CRBN-1

ePr

olife

ratio

n (fo

ld)

0

1.0***

CRBN

CD147

CUL1

MCT1

CRBN

WT

EV

CRBN

YW/A

A

0.20.40.60.8

DMSOLen.

MW(kDa)

35 –

55 –

55 –

40 –

40 –

MW(kDa)

35 –

55 –

55 –

40 –

90 –


Eichner et al.

lentiviral transduction with two independent shRNAs (sh_CRBN). Cells were treated with 10

µM lenalidomide (Len.) for 96 h as indicated.

(d) Immunoblot analysis of MM1S cells in which expression of CRBN WT or

CRBNYW/AA was induced by infection with respective lentiviral expression constructs.

(e) Cell proliferation analysis of parental (WT), and two CRBN–/– (T11, T21) MM1S

myeloma lines. Cells were treated with 10 µM lenalidomide (Len.) for 96 h as indicated (n = 3

independent experiments with two technical replicates each, data is presented as mean ± s.d.).

***, P < 0.001; one-sample t-test.


Eichner et al.

Supplementary Fig. 3. Lenalidomide destabilizes CD147 and MCT1 in a time and dose

dependent manner and particularly affects high glycosylated CD147.

(a) Immunoblot analysis of MM1S cells treated with 10 µM lenalidomide (Len.) for the

indicated times.

(b) Immunoblot analysis of MM1S cells treated with different concentrations of Len. for

72 h.

(c) Immunoblot analysis of MM1S cells treated with Len. (10 µM), the glycosylation

inhibitor tunicamycin (5 µg/ml; 48 h) or the N-glycan cleaving enzyme PNGase (10 U/µg

protein added to whole cell lysate). HG, high-glycosylated CD147; CG, core-glycosylated

CD147; NG, non-glycosyated CD147.

1,25 12,5 25 10050

CRBN

CD147

MCT1

CUL1

Len. (μM)0

IKZF3

a c

MW(kDa)

40 –

55 –

35 –

55 –

70 –

90 –

Len. treatmenttime (h)0 6 12 24 48 9672

IKZF3MCT1

CUL1

CD147 (SE)

CD147 (LE)

CRBN

HG

CG

55 –

35 –

55 –

35 –

55 –

40 –70 –

90 –

MW (kDa)

b

MCT1 (LE)

CRBN

IKZF3

CUL1

DMSO

PNG

ase

Len.

MCT1 (SE)

MW(kDa)

55 –

35 –

25 –

40 –

40 –

70 –

55 –

90 –

Tuni

cam

ycin

55 –

35 –

25 –

CD147 (LE)

HG

CG

NG

CD147 (SE)

HG

CG

NG


Eichner et al.

Supplementary Fig. 4. IMiD induced loss of CD147 and MCT1 expression is not observed in

mouse cells and is not regulated at the level of transcription.

(a) Immunoblot analysis of the murine myeloma line X63AG8.653 (X63) as well as

mouse Ba/F3 cells that were treated with 10 µM lenalidomide (Len.) or 100 nM

pomalidomide (Pom.) as indicated.

(b) Cell proliferation of mouse X63AG8.653 and Ba/F3 cells treated with Len. or Pom. as

specified, compared to control (DMSO) (n = 3 independent experiments with 2 technical

replicates each, data is presented as mean ± s.d.).

d

c

MCT1CRBN CD147

MM1.S

mRN

Aex

pres

sion(

fold)

0

0.5

1.0

1.5

2.0

CRBN CD147 MCT10

0.5

1.0

1.5

2.0

sh_s

cr

sh_I

KZF1

sh_I

KZF3

CRBN

CD147

MCT1 β-actin

IKZF1

IKZF3

0

0.5

1.0

1.5

Prol

ifera

tion

(fold

)

DMSO10 μM Len.100 μM Pom.

a b

U266 DMSO Len 10 μM

CD147

MCT1

CUL1

CK1-α

CRBN

Ponceau

β-actin

DMSO

X63 Ba/F3

Len.

Pom

.

DMSO

Len.

Pom

.

MW(kDa)

40 –

55 –

35 –

35 –

55 –

90 –

40 –

MW(kDa)

40 –

55 –

70 –

35 –

55 –

40 –

55 –


Eichner et al.

(c) Immunoblot analysis of MM1S cells in which IKZF1 and IKZF3 expression was

silenced by lentiviral transduction with the indicated shRNA constructs.

(d) Real-time qPCR analysis of MM1S and U266 cell lines treated with 10 µM Len. or

vehicle as specified. The amount of mRNA in the control sample was set as 1. (n = 3

independent experiments with two technical replicates each, data is presented as mean ± s.d.).


Eichner et al.

Supplementary Fig. 5. Characterization of the interaction of CRBN with CD147 and MCT1.

(a) Immunoprecipitation of Flag-tagged IKFZ3, CD147, and MCT1 from HEK293T

cells treated with lenalidomide as indicated. DSS was used for protein crosslinking. Bound

protein fractions were subjected to immunoblot analysis.

(b) Schematic of full-length human CD147 and MCT1 proteins and GST-tagged

fragments of their intracellular domains. T, transmembrane domain, IgI, immunoglobulin-like

domain.

(c) GST pull-downs of the indicated fragments of CD147 and MCT1 in whole cell

extracts (WCE) of MM1S cells. Precipitates were subjected to immunoblot analyses.

(d) Immunoprecipitation of HA-CUL4A that was purified from HEK293T cells and

incubated with MM1S cell extracts that were treated with lenalidomide or vehicle as specified.

Bound protein fractions were subjected to immunoblot analysis.

1- CD147 WT-269Igl Igl T

-269

T T1- -500 MCT1 WTT TT T T T T T T T T

-262

-500

GST-MCT1 (AA 188–262)GST-MCT1 (AA 444–500)

GSTGST

GST GST-CD147 (AA 230–269)

b

c

CRBN 35

25

WCE

GST

GST

-MCT

1 (A

A 18

8–26

2)

GST

-MCT

1 (A

A 44

4–50

0)

GST

-CD1

47 (A

A 23

0–26

9)

MW (kDa)

Ponceau

55

a

CRBN

EV IKZF3- +- - +- - +-

β-tubulin

IKFZ3/CD147/MCT1 (anti-Flag)CRBN

Len. IP

: ant

i-Fla

gW

CEEV CD147 EV MCT1

CRBN

CD147

MCT1

IKZF3

IP: anti-HA

WCE+ +--- -++

Len. - ++-CUL4A(anti-HA)

EVHA-CUL4A

DDB1

MW(kDa)

55 –

90 –

130 –

70 –

55 –

35 –

40 –

d


Eichner et al.

Supplementary Fig. 6. Cell surface expression of the CD147/MCT1 complex is CRBN-

dependent and is abrogated by lenalidomide.

(a) Visualization of HeLa cells stably expressing the indicated shRNA constructs and

transfected with expression constructs encoding HA-CD147 and Flag-MCT1. Cells were

incubated with an ER-tracker (blue) followed by fixation with paraformaldehyde and

ERMCT1 CD147 Merge

sh_C

RBN

sh_C

trl

a b

0

0.5

1.0

CD14

7 ex

pres

sion

(MFI

) *

DMSOLen.

CD147 DAPI MergeCRBN

MCT1 DAPI MergeCRBN

c

d

DMSO

Len.

DMSO

Len.


Eichner et al.

incubation with antibody to HA (green) and Flag (red). ER, endoplasmatic reticulum. Scale

bars, 10 µm.

(b) Cell surface expression of endogenous CD147 in MM1S cells treated with

lenalidomide (10 µM) as specified using flow cytometric analysis. Quantification of CD147

median fluorescence intensities (MFI) are shown presented as CD147/isotype ratios (n = 3

independent experiments, mean ± s.d.). *, P < 0.05; one sample t-test.

(c) Visualization of HeLa cells that were transfected with expression constructs

encoding HA-CD147 and Flag-CRBN and treated with lenalidomide (30 µM for 36 h ) as

specified. Cells were fixed with paraformaldehyde and incubated with antibody to HA (green)

and Flag (red). Scale bars, 10 µm.

(d) Visualization of HeLa cells that were transfected with expression constructs

encoding HA-MCT1 and Flag-CRBN, treated with lenalidomide (30 µM for 36 h) as

specified, and processed as in (c). Scale bars, 10 µm.


Eichner et al.

Supplementary Fig. 7. CRBN mediated maturation of the CD147/MCT1 complex is

abrogated by lenalidomide.

(a) Immunoprecipitation (IP) of Flag-CD147 from whole cell extracts (WCE) of MM1S

cells that were treated with cycloheximide (CHX) for the indicated times before lysis. Bound

protein fractions were analyzed by immunoblotting. The asterisk denotes unspecific bands.

(b) Immunoprecipitation of Flag-MCT1 from whole cell extracts of MM1S cells that were

treated as in (a). Bound protein fractions and whole cell extracts analyzed by immunoblotting

are shown.

(c) Immunoprecipitation of Flag-MCT1 with endogenous CD147 (left) or Flag-CD147

with endogenous MCT1 (right) from HEK293T cells in which CRBN expression was induced

by a CRBN expression construct. Immunocomplexes were probed with antibodies to the

indicated proteins.

(d) Autoradiographic analysis of CD147 immunoprecipitates from MM1S cells that were

pulsed with 35S Met/Cys, treated with lenalidomide (10 µM) and/or the glycosylation

inihibitor tunicamycin (10 µM) as indicated, and chased for the specified times. CG, core

glycosylated; HG, high glycosylated (mature form).

a b

CUL1

CD147

MCT1 (anti-Flag)

IP: anti-FlagCRBN+-

CRBN

WCE- +--

MCT1

CD147 (anti-Flag)

IP: anti-FlagCRBN+-

CRBN

WCE- +--

CUL1

0

35 –

24

+ Len.– Len.

0 1 3 6 24 24 1 3 246 Time (h)+ Glyc. Inhib.

S35 Autoradiogram

MW (kDa)

55 –CD147

HG

CG

CRBN

MCT1 (anti-Flag) 0 0.5 1 2 4

IP:

anti-

Flag

WCE

CHX treatment time (h)60Flag-MCT1+ + + + + +-

CRBN MCT1 (anti-Flag) *

CRBN

CD147(anti-Flag)

0 0.5 1 2 4IP

: ant

i-Fla

gW

CECHX treatmenttime (h)

60Flag-CD147+ + + + + +-

CRBN

CD147 (anti-Flag) *

*

c

d

MW(kDa)

35 –

55 –

55 –

55 –

35 –

55 –

MW(kDa)

55 –

40 –55 –

40 –

MW(kDa)

35 –

40 –

55 –

90 –

55 –

MW(kDa)

35 –

40 –

55 –

55 –

90 –


Eichner et al.

Supplementary Fig. 8. Analysis of lenalidomide-sensitive and -resistant MM cell lines and

primary patient derived MM cells.

(a) Quantification of the CD147 and MCT1 protein expression levels of immunoblots

b

CD14

7 ex

pres

sion

(fold

)

0

0.5

1.5

1.0

a

e

** * ** **

DMSOLen.

MCT

1 ex

pres

sion

(fold

)

0

0.5

1.5

1.0

DMSOLen.

** * ** **

f

Intra

cellu

larla

ctat

e(fo

ld)

0

0.5

1.5

1.0

2.0*

*

sh_Ctrlsh_CRBNsh_MCT1

0

0.4

1.0

0.2

0.6

0.8

VEG

F se

cret

ion

(fold

) sh_Ctrlsh_CRBNsh_CD147sh_MCT1

*******

0

20

40

60

80

Anne

xinV–

& PI

–(%

)

0

20

40

60

80

dLensens Lenres

*

c

MCT1

CD147

KMS12BM

RPMI8226

sh_Ctrlsh_CD147sh_MCT1

+--

-+-

--+

+--

-+-

--+

U266+--

-+-

--+

MM1S+--

-+-

--+

AMO1+--

-+-

--+

L363+--

-+-

--+

Lensens Lenres

CUL1

MW(kDa)

35 –

40 –

55 –

90 –

CUL1

MCT1

CRBN

sh_Ctrlsh_CRBNsh_MCT1

+––

–+–

––+

MW(kDa)

90 –

40 –

55 –

CUL1MCT1

CRBN

sh_Ctrlsh_CRBNsh_CD147sh_MCT1

+––

–+–

––+

–––

– – – +

CD147

MW(kDa)

35 –

40 –

55 –

90 –

55 –

**

02040

6080

100

0

100

50

150

Lensens Lenres

CD14

7 ex

pres

sion

(MFI

)

CD14

7 ex

pres

sion

(MFI

)

020406080

100

0

50

100

150

Anne

xinV–

& PI

–(%

)


Eichner et al.

shown in Fig. 3a averaged with two additional independent experiments (n = 3 independent

experiments, mean ± s.d.). *, P < 0.05; **, P < 0.01; one sample t-test.

(b) Immunoblot analysis of the indicated lenalidomide-sensitive and -resistant MM cell

lines, in which CD147 and MCT1 were silenced using the specified shRNAs. The

corresponding proliferation analysis is presented in Fig. 3c.

(c) Cell surface expression (MFI, median fluorescence intensity) of CD147 in purified

primary CD138 positive MM cells derived from patients with either lenalidomide sensitive or

resistant diesease using flow cytometric analysis and treated with lenalidomide or DMSO for

48 h. Bar graphs show cumulative MFI ratios of Len. relative to DMSO (left), next to

individual absolute MFI values (right) (len. sensitive: n = 5 subjects, len resistant: n = 5

subjects; mean ± s.e.m.). **, P < 0.01; one-sample t-test.

(d) Flow cytometric analysis (annexin V / PI) of cells described in (c) (len. sensitive: n

= 5 subjects, len resistant: n = 5 subjects; mean ± s.e.m.). *, P < 0.05; Student’s t-test.

(e) Analysis of intracellular lactate levels in MM1S cells in which CRBN or MCT1 were

silenced by the specified shRNAs (left) (n = 4 independent experiments, mean ± s.d.). *, P <

0.05; one-sample t-test. Representative immunoblot analysis of the respective cells (right).

(f) Analysis of VEGF secretion in MM1S cells in which CRBN, CD147 or MCT1 were

silenced by the specified shRNAs (left) (n = 5 independent experiments, mean ± s.d.). **, P <

0.01; ***, P < 0.001; one-sample t-test. Representative immunoblot analysis of the respective

cells using the specified antibodies (right).


Eichner et al.

Supplementary Fig. 9. Expression of CD147 on CD45low/CD235α+ erythropoiesis in MDS

bone marrow of representative non-del(5q), untreated del(5q) and lenalidomide treated del(5q)

patient samples.

Shown are representative plots from subjects #5, #13 and #28 (see Supplementary

Table 2). Using a CD45 and SSC gating strategy, the gate was set on CD45low cells with low

SSC properties. Next, CD34 expressing and CD235α expressing cells within this gate were

discriminated and an analysis gate was set on CD235α+ cells. CD147 expression of

CD45lowCD235α+ cells was determined by histogram gating. Shaded histograms, IgG isotype

control; red histograms, CD147.

SSC

CD459.71

Del(5q)CD34

CD235α21.2

21.1 54.3

Count

CD147

CD45low CD34low/CD235α+

SSC

CD4528.4

Del(5q):+:Len.

CD34

CD235α9.36

22.0 66.8

Count

CD147


SSC

CD456.69

Non?del(5q)

CD34

CD235α18.3

0.057 76.2

Count

CD147



Eichner et al.

Supplementary Fig. 10. CD147 and MCT1 expression is independent of CK1-α in del(5q)

and non-del(5q) MDS cells.

Immunoblot analysis using the specified antibodies of the indicated MDS cell lines, in

which CK1-α was silenced by the specified shRNAs.

CD147 (SE)

MCT1 (LE)

MCT1 (SE)

CK1-α

CRBN

CD147 (LE)

sh_Ctrlsh_CK1-α_1sh_CK1-α_2

+ - - + - -- + - - + -- - + - - +

MDSLdel(5q)

SKKnon-del(5q)

β-actin

55 –

35 –

35 –

40 –

40 –

MW (kDa)

55 –

35 –

55 –

40 –


Eichner et al.

Supplementary Fig. 11. Analysis of zebrafish injected with CD147 morpholinos or treated

with different IMiDs.

(a) Semiquantitative RT-PCR on cDNA extracted from zebrafish injected with CD147

splice morpholino (targeting the border of exon3/intron3) at the indicated concentrations or

control. PCR was performed with CD147 fw primer in exon 3 and CD147 rv primer in exon

5, or β-actin primers as control.

(b) Real-time qPCR analysis on cDNA from zebrafish described in (a). qPCR was

performed with CD147 fw primer in exon 3 and CD147 rv primer in exon 4 to detect spliced

mRNA. The amount of mRNA in the control sample was set as 1. (n = 3 independent

experiments with two technical replicates each, mean ± s.d.). ****, P < 0.0001; one-sample t-

test.

CD147 splice MO

unspliced(ex3–ex5: 2387 bp)

spliced(ex3–ex5: 341 bp)

CD14

7

500 bp

1000 bp

1500 bp

2000 bp

β-actin500 bp

a b

c

zf CD147 (SE)

Ponceau

zf CD147 (LE)

0 0.1 0.25 0 0.1 0.25

CD147 splice MO

CD147 ATG MO

μM

****

0

0.5

1.0 ****

CD14

7 m

RNA

0 0.1 0.25 mM

d

0

0.5

1.0

1.5

CD14

7 pr

otein

expr

essio

n(fo

ld) **55 –

35 –

MW (kDa)

55 –

35 –


Eichner et al.

(c) Immunoblot analysis of zebrafish larvae at 3 dpf that were injected with the indicated

CD147 morpholinos as specified.

(d) Quantification of zebrafish CD147 protein expression levels of immunoblots shown

in Fig. 6f averaged with two additional independent experiments (n = 3 independent

experiments, mean ± s.d.). Extracts were derived from zebrafish larvae treated with DMSO or

the indicated IMiDs. **, P < 0.01; one-sample t-test.


Eichner et al.

Supplementary Table 2. MDS patients’ characteristics.

RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory

cytopenia with multilineage dysplasia and ring sideroblasts; RAEB, refractory anemia with

excess blasts IPSS, International Prognostic Scoring System; INT1, intermediate 1; INT2,

intermediate 2.

Patient' sex' age' WHO'subtype' cytogenetics' IPSS' Under'lenalidomide'

treatment'1' m" 57" RAEB1" 46"XY"t(8;10)" INT1" "2' m" 72" RAEB1" 47,"XY,"+8" INT1" "3' w" 58" RAEB1" 46"XX" INT1" "4' w" 70" RAEB1" 46"XX" INT1" "5' w" 67" RARS" 46"XX" low" "6' w" 71" RCMD" 46"XX" INT1" "7' m" 74" RCMD" 46"XY" INT1" "8' m" 74" RCMD" 46,"XY" low" "9' m" 66" RAEB1" 46"XY" INT1" "10' w" 42" RCMDARS" 46"XX" low" "11' w" 60" RA" 46"XX" low" "12' w" 73" RCMD" 46"XX,"del(5q)" INT1" "13' w" 79" RCMD" 46"XX"del(5q)" low" "14' w" 72"" RCMD" 46"XX"del(5q)" low" "15' w" 74" RCMD" 46"XX"del(5q)" low" "16' m" 72" RCMD" 46"XY,"del(5q)" low" "17' w" 79" RCMD" 46"XX"del(5q)" low" "18' w" 74" RCMD" 46"XX"del(5q)" low" "19' m" 69" RCMD" 46"XY"del(5q)" low" "20' w" 72" RCMD" 46"XX"del(5q)" low" "21' w" 74" RCMD" 46"XX"del(5q)" low" "22' m" 65" RAEB1" 46,"XX"del(5q),A7" INT2" "23' m" 68" RCMD" 46,"XY"del(5q)" low" "24' w" 82" ""RAEB1" 46,"XX"del(5q)" INT1" x"25' w" 65" "RCMD" 46,"XX"del(5q)" low" x"26' w" 67" "RCMD" 46"XX"del(5q)" low" x"27' w" 80" RCMD" 46"XX"del(5q)" low" x"28' w" 52" RCMD" 46,"XX"del(5q)" low" x"29' w" 77" RCMD" 46,"XX"del(5q)" low" x"30' w" 79" RCMD" 46"XX"del(5q)" low" x"31' w" 72" RCMD" 46"XX"del(5q)" low" x"32' w" 73" RCMD" 46"XX"del(5q)" low" x"33' w" 54" RAEB1" 46"XX"del(5q)" INT1" x"


supplementary information immunomodulatory drugs … · ev 1 ev 1 crbn mct1 ... scr 1 3 crbn cd147...

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