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DIFFERENTIATION THERAPY OF APL

DIFFERENTIATION THERAPY OF APL. . Retinoic acid and arsenic trioxide . Differentiation into granulocytes . Best prognosis among myeloid leukemias (Cure rates: 30% in 1988, 70% 2003, 100% very soon ) . First example of differentiation therapy. Huang, Blood 1988, Chen Blood 1996.

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DIFFERENTIATION THERAPY OF APL

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  1. DIFFERENTIATION THERAPY OF APL . Retinoic acid and arsenic trioxide . Differentiation into granulocytes . Best prognosis among myeloid leukemias (Cure rates: 30% in 1988, 70% 2003, 100% very soon ) . First example of differentiation therapy Huang, Blood 1988, Chen Blood 1996

  2. THE t(15;17) TRANSLOCATION . Specific for APL . Rearranges the RARa gene into a PML/RARa fusion . PML/RARa expression in transgenic mice suffice to induce APL . Rare variant translocations, all involving RARa . First example of oncogene-targeted therapy de Thé Nature 1990, de Thé Cell 1991

  3. Combining RA/As in the mouse • Transgenic mice develop APL • RA-induced differentiation to granulocytes • Demonstrates Arsenic trigger differentiationin vivo (apoptosis ex vivo, no differentiation) • RA/As synergy for disease regression (model and cell line studies had predicted antagonism)

  4. Lallemand JEM 1999

  5. APL PATIENTS ? No relapse un dual-treated patients, Arsenic better than RA! 60/61 CR Chen PNAS 2004

  6. AGGTCA ER3-8 PML/RARA-SPECIFIC REPORTERS Fold induction APL: RARA, PML/RARA by RA Non-APL: RARA 50 40 30 20 10 1 1 2 3 4 5 6 8 10 12 16 0 8 DR IR ER DR1-16 IR0 Kamashev JEM 2004

  7. Major gain of function, PML/RARA controls genes not regulated by RA in non-APL cells • PML/RARA-specific reporters: test the real effects of RA exclusively on the fusion in APL cells

  8. Fold induction 50 40 30 20 10 1 RA, 10nM cAMP DR5 DR8 DR10 cAMP/RA CROSS-TALKS • Well-known for APL & F9 differentiation, but never demonstrated for transcriptional activation by RARA and PML/RARA

  9. CONCLUSIONS (cAMP) • cAMP functionally targets PML/RARA Enhances differentiation by RA and As Enhances RA activation of PML/RARA- specific reporters genes • Reverts RA-resistance ex vivo and in vivo • Clinically relevant: Theophyline first line drug?

  10. 7 6 nls-PML/RARAK160R 5 Number of mice line with myeloproliferation 4 3 2 1 0 0 5 10 15 20 25 Months MYELOPROLIFERATION IN PML/RARA-K160R TG MICE

  11. SPLENOMEGALY APL 6/8 LINES 7/8 LINES PML/RARA PML/RARA K160R 0/10 LINES 10/10 LINES IRRADIATED SPLENOMEGALY But no progression towards APL APL UNIRRADIATED GRAFT 1 GRAFT 2 n°4 n°16 (4/4) PML/RARA n°17 (4/4) n°23 (3/3) n°26 (9/9) GRAFT 2 GRAFT 1 n°14 n°22 (1/4) n°24 nls-PML/RARAK160R (1/4) n°27 (1/5) n°30 (1/5) 30 35 40 5 0 10 15 20 25 Months

  12. CONCLUSIONS (K160) • PML/RARA homodimers do not suffice to induce a differentiation block and do not trigger APL • PML sumolation critical to differentiation block and immortalisation, most likely through Daxx-triggered repression • Could explains why PML is the common fusion partner in APL

  13. A sad note to finish • Despite the absence of any basic or clinical research and the low manufacturing costs, Arsenic sells it for over 100 000 E for a complete treatment • Most countries, including France, cannot afford it for first line patients, despite its obvious superiority • We may have failed just when we thought we had succeeded...

  14. CREDITS CNRS 9051, Hôpital St. Louis, Paris Jun ZHU, Jun ZHOU, Florence RIAUCOUX, Laurent PERES, Nicole HONORE, Marie-Claude GUILLEMIN, Valérie LALLEMAND, Hassane SOIHILI, Dmitrii KAMASHEV, Dominique VITOUX Hôpital St. Louis, Paris Emmanuel RAFFOUX, Hervé DOMBRET, Marie-Thérèse DANIEL, Michel LANOTTE , Laurent DEGOS USCF: Scott KOGAN, Mike BISHOP Pôle Franco-Chinois de Shanghai: Zhu CHEN

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