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CRLF2 PowerPoint Presentation

CRLF2

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CRLF2

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  1. 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

  2. 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

  3. DS-ALL: JAK2 mutation in 20% • All involve R683 and different from V617F/ other MPNs mutations.

  4. JAK2 Pseudokinase Domain (Model) Arg683 (B-ALL) Val617 (MPNs) Gilad Wainreb, Nir Ben-Tal

  5. 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

  6. 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

  7. 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.

  8. CRLF2 (TSLPR) CRLF2 From Nature Immunol. 2009; 7: 709–714

  9. Mechanism of abberant CRLF2 expression FISH analysis Interphase Interphase Metaphase Metaphase IGH@ translocation (14q32) Deletion Xp22.3/ Yp11.3 RT-PCR analysis

  10. IL7RA CRLF2 Does IL7RA also over-expressed? FACS analysis CRLF2 Maike Schmitz

  11. Do JAK2 mutations and CRLF2 over-expression related?

  12. Functional cooperation CRFL2 and JAK2 No requirement for IL7RA

  13. What happen in high CRLF2 without JAK2 mutations? Mutational screen of CRLF2

  14. F232C

  15. F232C- An activating mutation in CRLF2

  16. A model for DS-ALL 3rd event 1ST event 2nd event Down syndrome Clinical Significance?

  17. CRLF2 prognostic significance-DS-ALL (log rank test, p=0.12) Hertzberg et al Blood 2009

  18. CRLF2 prognostic significance-Childhood HR-ALL BCR-ABL MLL neg Harvey et al Blood 2010

  19. CRLF2 prognostic significanceAdult HR-ALL (BCR/ABL MLL neg) Yoda et al. PNAS 2009

  20. Therapeutic implications?JAK inhibitors? CRLF2 inhibitors?

  21. 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