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Regulation of multiple myeloma cell differentiation by bone-marrow derived microenvironmental factors. Nili Dezorella Tel - Aviv University Sackler Faculty of Medicine Tel-Aviv Souraski Medical Center Tel-Aviv, Israel. Multiple myeloma. Plasma cell proliferation CD138+\CD38+\CD45-\CD19-.

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slide1

Regulation of multiple myeloma cell differentiation by bone-marrow derived microenvironmental factors

Nili Dezorella

Tel - Aviv University

Sackler Faculty of Medicine

Tel-Aviv Souraski Medical Center

Tel-Aviv, Israel

slide2

Multiple myeloma

Plasma cell proliferation CD138+\CD38+\CD45-\CD19-

Monoclonal Ig in blood and/or urine (most cases)

Lytic bone lesions

slide3

MM therapy

Many anti-MM drugs available

Diverse therapeutics: steroids, chemotherapy,

immunomodulators, targeted therapy, BMT – endless

combinations

Novel experimental drugs

Still – no cure

Is there an answer in the biology of MM ?

slide6

Co-culture experiments (7d)

MM cells

(CAG cell line)

Flow cytometry

CD38 (+)

CD138 (+)

CD45 (-)

Light chain (+ kappa)

Mesenchymal Stromal Cell (MSC)

slide10

Mesenchymal stroma down-regulates plasma cell markers

1.2

1.2

1.0

1.0

0.8

0.8

Ratio MFI stroma/control in MM cells

Ratio MFI stroma/control in MM cells

0.6

0.6

0.4

0.4

0.2

0.2

Kappa

CD38

CD138

slide11

Soluble

factors

Adhesive

interactions

slide12

Regulation of CD38 expression

P<0.00001

160

120

P<0.0001

CD38 Mean FL intensity

80

40

Culture

Insert

Control

+ Stroma

slide13

300

250

200

Mean FL intensity

150

100

P<0.005

50

Regulation of CD138 expression

Culture

Insert

Control

+ Stroma

slide14

Stromal cultures conditioned medium

CD38

CD138

Medium

Counts

Counts

Control

Stroma

Fluorescence intensity

Fluorescence intensity

slide15

What are the stromal-derived soluble factors

that regulate CD38 expression ?

Two major candidates: SDF-1, IL-6

1.2

1.0

0.8

control

0.6

CD38 treated/control

stroma

0.4

0.2

0.0

AMD 3100

SDF-1\CXCR4 inhibitor

slide16

control

IL-6 (1 ng/ml)

IL-6 down regulates CD38 in MM cells

Number of events

CD138

CD38

kappa

slide17

1.4

1.2

1.0

0.8

0.6

0.4

0.2

IL-6 mediates stromal down regulation

of CD38 in MM cells

Ratio CD38 MFI stroma experiment\

CD38 MFI CAG cells

Control

stroma

No Ab

1 mg/ml

5 mg/ml

1 mg/ml

5 mg/ml

Anti IL-6 mAb

Control mAb

slide18

1.8

1.4

1.0

0.6

0.2

1.4

1.0

ARH-77

U266

RPMI

8226

MM1S

CAG

Avg.

+S.D.

0.6

0.2

Regulation of MM markers-

Various MM lines

CD38

Ratio MFI stroma/control in MM cells

CD138

slide19

700

600

500

400

300

200

100

0

Ex vivo propagation of MM cells

~15 days

7

P=0.002

P=0.007

6

5

CD38 (mean FL intensity)

4

Ratio aspirate\ex vivo

3

2

1

0

CD38

CD138

Aspirate

Ex vivo

slide20

Bone marrow aspirate of MM patient

Spicules – adherent cells

Fluid phase – floating cells

slide21

101

102

103

101

102

103

Mechanical

+ enzymes

103

Adherent MM cells

in a patient BM

102

101

Mechanical

103

No of events

102

CD38

101

CD138

Soluble

103

102

101

CD138

slide22

Conclusions

  • The stroma reduces significantly cell surface markers of MM cells
  • The stroma reduces surface Ig expression.
  • CD38 reduction – soluble factor(s) – probably IL-6
  • CD138 reduction – adhesion dependent

The stroma may induce de-differentiation of malignant plasma cells by combined activity of mediators

slide23

Normal plasma cells

Accelerated differentiation

Apoptosis

End of life cycle

De-differentiation

Ab production & secretion

Retain viability

slide24

Multiple myeloma

De-differentiation

Ab production & secretion

Retain viability

slide27

Dr. Bentzi Katz

Shoshie Baron

Ruth Stern

Prof. Ella Naparstek

The Hematology Institute

TASMC

Prof. Benny Geiger

Prof. Dov Zipori

Weizmann Institute

of Science

Prof. Arnon Nagler

Sheba Medical Center