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Are all APL screated equal?
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Background
• RARαtranslocations in acute promyelocyticleukemia (APL)
• Mouse models recapitulate the human phenotype
• Current treatments utilize retinoic acid (RA) to induce differentiation and arsenic trioxide to induce apoptosis
• Human patients have variable response to therapy
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Retinoic acid (RA) and As2O3treatment in transgenic models of acute promyelocyticleukemia (APL) unravel the distinct nature of the leukemogenicprocess induced by the PML-RARαandPLZF-RARαoncoproteins
EduaroM. Rego, Li-Zhen He, Raymond P. Warrell, Jr., Zhu-Gang Wang, and Pier Paolo Pandolfi
Proc. Natl. Acad. Sci. USA97, 10173-10178
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Fig. 1. Effects of treatment with As2O3, RA, or As2O3 + RA on the survival of leukemicTM PML-RAR[alpha] and PLZF-RAR[alpha]
Rego,E. M., et al. "Retinoic Acid (RA) and As2O3 Treatment in Transgenic Models of Acute PromyelocyticLeukemia(APL) Unravel the Distinct Nature of the LeukemogenicProcess induced by the PML-RARalphaand PLZF-RARalphaOncoproteins." PNAS 97, no. 18 (August 29, 2000): 10173-8. Copyright 2000 National Academy of Sciences, U.S.A. Used with permission.
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Questions remaining:
• What are the inherent differences/similarities between PML-RARαand PLZF-RARαat the molecular level?
• How/why does PLZF-RARαrespond differently to RA?
• Is expression of PLZF-RARαrequired for tumor maintenance?
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What are the inherent differences between PML-RARaand PLZF-RARaat the molecular l
evel?
• Gene expression analysis on random APLsfrom humans followed by identification of the fusion gene
• Correlate gene expression in PML-RARαvs. PLZF-RARαvs. normal myeloid cells
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Possible results: Common genetic pathways upregulated
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How/why does PLZF-RARarespond differently to RA?
• Additional analysis of gene expression profiles generated in previous section.
• New gene expression analysis comparing cultured PML-RARα± RA and PLZF-RARα± RA.
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Possible results: Inhibition of Hox signaling
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*: HoxB3 inhibits differentiation →normal & PML do not express B3
*: HoxD4 promotes differentiation →PLZF does not express D4 or B4
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Is expression of PLZF-RARarequired for tumor maintenance?
• Tetracycline-regulated transgenic expression
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Possible results