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Signal transduction and transcription regulation in the development of blood cells and leukemia

Signal transduction and transcription regulation in the development of blood cells and leukemia. Ruibao Ren Brandeis University Waltham, MA. COMMON LYMPHOID PROGENITOR. B. T. NK CELL. LONG-TERM REPOPULATING MULTIPOTENTIAL PROGENITOR. Hematopoiesis. SHORT-TERM REPOPULATING

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Signal transduction and transcription regulation in the development of blood cells and leukemia

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  1. Signal transduction and transcription regulation in the development of blood cells and leukemia Ruibao Ren Brandeis University Waltham, MA

  2. COMMON LYMPHOID PROGENITOR B T NK CELL LONG-TERM REPOPULATING MULTIPOTENTIAL PROGENITOR Hematopoiesis SHORT-TERM REPOPULATING MULTIPOTENTIAL PROGENITOR COMMON MYELOID PROGENITOR M B N E RBC PLATELETS

  3. BCR/ABL HSC CMP CLP GMP MEP ? ? CML-BP (Myeloid) CML-BP (Lymphoid) MEG G M RBC PLATELETS T-CELL B-CELL CML-CP Chronic myelogenous leukemia (CML)

  4. Mouse Bone Marrow Transduction/Transplantation 5’ LTR Murine stem cell virus (MSCV) vector - able to drive transgene expression in HSC cells. 3’ LTR IRES BCR/ABL gfp lethal irradiation BOSC23 (gag, pol and env) 2 days 2 days 4 days infect twice (SCF, IL-3, IL-6) 5-FU

  5. 100 80 60 40 20 0 Survival Curves for BCR/ABL and control mice Vector (n = 5) Survival rate (%) BCR/ABL wt (n = 11) 0 10 20 30 300 Days after BMT

  6. Elevated white blood cell (WBC) counts in BCR/ABL mice Vector mouse BCR/ABL mouse (372.4 ± 75.1)x1000/µl (19.5 ± 4.5)x1000/µl

  7. Research area I: Identification of critical targets of BCR/ABL in the pathogenesis of CML

  8. PH Dbl DBD Y177 Y1294 BCR/ABL PP PP PP SH3 SH2 Y-KINASE NLS ABD CC Grb2 Ras-GDP Gab2 Shp-2 PI-3K Ras-GTP ? Sos 100 80 Vector control n=4 60 Survival rate (%) BCR/ABL n=7 (CML-like MPD) 40 BCR/ABL-Y177F n=14 (T cell leukemia/lymphoma) 20 0 0 50 100 150 200 Days post-BMT Y177 of BCR/ABL is necessary for induction of the fatal MPD

  9. (CML) BCR/ABL Grb2 PI3K Gab2 (CML) BCR/ABL (JMML) SHP-2 Grb2 ? Neurofibromin (JMML) Ras-GTP (CMML, JMML, AML, MDS) MEK1/2 Extracellular signals Ras-GDP Sos p120 GAP RasGRF Neurofibromin RasGRP Ras-GTP AF6 IMP Raf Tiam1 RalGEF p120GAP RIN NORE1 PLCe PI3K KSR ? Rac profilin MST1 Ral Rab5 PIP2 PIP2 DAG + IP3 PIP3 ERK1/2 PKC Ca-- PTEN Akt

  10. Research area II: Ras signaling in leukemogenesis

  11. 1 2 myc-N-RasD12 endogenous Ras -Ras blot Vector control LTR IRES GFP LTR -myc tag blot N-RasD12 GFP IRES LTR LTR N-RasD12 -actin blot NIH 3T3 Oncogenic N-Ras induces myeloid leukemia in mice 1 .8 .6 Vector control (n=5) .4 N-RasD12-HT (n=12) Cum. Survival .2 N-RasD12-LT (n=12) 0 0 20 40 60 80 100 Days post-BMT

  12. Interferon (IFN)- therapy • Before imatinib myselate, the standard treatment for the chronic phase of CML was IFN-, which induces a complete or nearly complete cytogenetic response in 10 to 30 percent of patients. • Complete remission is achievable in significant portion of IFN- responsive patients after stopping administration of IFN-. • IFN- has higher toxicity to the more primitive CML progenitors than imatinib.

  13. IRF-4 is a potent myeloid tumor suppressor. • Mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive CML-like disease than mice deficient in IRF-8 alone. • Forced expression of IRF-4 suppresses BCR/ABL-induced CML-like disease in mice.

  14. Research area III: Mechanism of tumor suppression by IRF4/8

  15. Research area IV: Mechanism of blast transformation of CML

  16. Summary of mouse models for myelogenous leukemias disrupting transcription regulation impairs hematopoiesis (MDS) AME AML CML-like MPD BCR/ABL activating growth factor receptor signaling long latency (5-13 months) (not sufficient to block myeloid differentiation) (does not block myeloid differentiation) short latency Activating growth factor signaling pathways (e.g. BCR/ABL) Disrupting hematopoietic transcription regulation (e.g. AME) uncontrolled growth + block of myeloid differentiation BCR/ABL + AME AML short latency Proliferation Survival Blocking myeloid cell differentiation Oncogene cooperation in the pathogenesis of myeloblastic leukemia

  17. Integrative cancer research

  18. A Hours of Treatment 24 24 24 24 ATO(M) - 0.5 1.0 2.0 AME Dynamin GFP Relative Ratio: AME/Dyn 1.0 0.85 0.32 0.22 B Hours of Treatment 72 72 72 72 - 0.5 1 2 ATO(M) AME Dynamin GFP Relative Ratio: AME/Dyn 1.0 0.40 0.15 N/D ATO induces downregulation of AME in BM6-4 cells BM6-4 cells, a primary AME leukemic cell line derived from bone marrow cells of a mouse with AME-induced AML and grown in the presence of IL-3 or GM-CSF.

  19. Research area V: Mechanism of targeted degradation of EVI1

  20. Acknowledgments Xiaowu Zhang Alec Gross Samanthi Perera Catherine Spicer Ramesh Subrahmanyam Grace Cuenco Xiujuan Ho Yongli Ji Jaime Acquaviva Jessica Fredericks Chaitali Parikh David Shackelford Benjamin Cuiffo Brandeis University Collaborators: Warren Pear University of Pennsylvania Giuseppina Nucifora Loyola University Medical Center Samuel Waxman Mount Sinai School of Medicine

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