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CRLF2. CRLF2- a new player in ALL Ithamar Ganmore, Libi Hertzberg Shai Izraeli’s lab Cancer Research Center, Sheba Medical Center, Tel-Aviv University Israel Society of Hematology and Blood Transfusions annual conference- 16.2.2010. Down syndrome & Leukemia. Chromosome 21 and Leukemia.

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Crlf2

CRLF2

CRLF2- a new player in ALL

Ithamar Ganmore, Libi Hertzberg

Shai Izraeli’s lab

Cancer Research Center, Sheba Medical Center, Tel-Aviv University

Israel Society of Hematology and Blood Transfusions annual conference- 16.2.2010


Crlf2

Down syndrome & Leukemia

Chromosome 21 and Leukemia

DS-ALL

(2-3%)

Constitutional tirsomy 21

HHD

(10-25%)

(High Hyperdiploid)

Most cases with 4 copies of chr. 21

TEL-AML1

(25%)

AML is on Chr. 21

  • (Less solid tumors)

  • X600 AMKL

  • X20 ALL

  •  cT21 is leukemogenic


Crlf2

  • DS-ALL: JAK2 mutation in 20%

  • All involve R683 and different from V617F/ other MPNs mutations.


Crlf2

JAK2 Pseudokinase Domain (Model)

Arg683

(B-ALL)

Val617

(MPNs)

Gilad Wainreb, Nir Ben-Tal


Crlf2

  • DS-ALL: JAK2 mutation in 20%

  • All involve R683 and different from V617F/ other MPNs mutations.

  • The mutations are acquired, expressed, activate JAK2

  • Sensitive to JAK inhibitors


R683 jak2 transform baf3 cells

Wild type JAK2

R683 JAK2 transform Baf3 cells

Only with EPOR or TPOR

Hypothesis – constitutional trisomy 21 associated with B linage expression of a type I cytokine receptorcooperating with R683 mutated JAK2


Crlf2

DS-ALLs gene expression profile

  • CRLF2 (cytokine receptor like factor 2)=

  • TSLPR (Thymic stroma-derived lymphopoietin receptor)

  • Located at the pseudoautosomal region of the sex chromosomes.


Crlf2

CRLF2 (TSLPR)

CRLF2

From Nature Immunol. 2009; 7: 709–714


Crlf2

Mechanism of abberant CRLF2 expression

FISH analysis

Interphase

Interphase

Metaphase

Metaphase

IGH@ translocation

(14q32)

Deletion

Xp22.3/ Yp11.3

RT-PCR analysis


Crlf2

IL7RA

CRLF2

Does IL7RA also over-expressed?

FACS analysis

CRLF2

Maike Schmitz


Crlf2

Do JAK2 mutations and

CRLF2 over-expression related?


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Functional cooperation CRFL2 and JAK2

No requirement for IL7RA


Crlf2

What happen in high CRLF2 without JAK2 mutations?

Mutational screen of CRLF2


Crlf2

F232C


Crlf2

F232C- An activating mutation in CRLF2


Crlf2

A model for DS-ALL

3rd event

1ST event

2nd event

Down syndrome

Clinical Significance?


Crlf2 prognostic significance ds all

CRLF2 prognostic significance-DS-ALL

(log rank test, p=0.12)

Hertzberg et al Blood 2009


Crlf2 prognostic significance childhood hr all bcr abl mll neg

CRLF2 prognostic significance-Childhood HR-ALL BCR-ABL MLL neg

Harvey et al Blood 2010


Crlf2 prognostic significance adult hr all bcr abl mll neg

CRLF2 prognostic significanceAdult HR-ALL (BCR/ABL MLL neg)

Yoda et al. PNAS 2009


Therapeutic implications jak inhibitors crlf2 inhibitors

Therapeutic implications?JAK inhibitors? CRLF2 inhibitors?


Crlf2

Special Thanks

Sheba

Libi Hertzberg

Ruthy Shiloh

Italy

E Vendramini

G te Kronnie

G Cazzaniga

I Iacobucci

Our collaborators:

Yehudit Birger

Sharon Zeligson

Gidi Rechavi

Elad Ben-Meir

Weizmann

Eytan Domany

Libi Hertzberg

MIGAL

Chen Shochat

Arava Elimelech

Dani Bercovich

UK

J Chalker

H Kempski

LJ Russell

C Harrison

Germany

G Cario

M Stanulla

A Borkhardt

Austria

S Strehl

Czech Repub

J Trka

Switzerland

M Schmitz

B Bornhauser

JP Bourquin

Tel Aviv University

Gilad Weinrab

Nir Ben Tal

Anat Taragan

Yoel Kloog

SCMC

Batia Stark

Smadar Avigad

iBFM-Study Group

Support: ISF; WCRF; IL Science and Health Ministries; Wolfoson Foundation; JNF UK


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