1 / 22

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. Down syndrome & Leukemia. Chromosome 21 and Leukemia.

myrrh
Download Presentation

CRLF2

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related