Transcriptional repression of the rara pathyway is crucial for leukemogenesis

Mantu Bhaumik, Austin C. Changou, Eduardo M. Rego, Arthur Zelent, Wilson Miller, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

Abstract

Retinoids play a key role in the control of differentiation and proliferation in the myeloid compartment. Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving the RARa gene which variably fuses to one of several distinct loci, including PML or PLZF (X genes). As a consequence, X-RARa and RAR(X-X fusion proteins coexist in APL blasts. t(15;17) APL responds to retinoic acid (RA), while t(l 1:17) APL does not. The X-RARa fusion proteins are able to homo and heterodimerize with the respective X proteins, thus interfering with their pathways. XRARa can also bind RA and DNA through the RARa ligand and DNA binding domains, thus acting as aberrant versions of RARa. X-RARa proteins are unresponsive to physiological dose of RA. While at these doses RARo/RXR would activate transcription, the X-RARa oncoproteins act as potent repressers. Pharmacological doses of RA can restore the ability of PML-RARa to activate transcription thus triggering differentiation, while PLZF-RARa remains unresponsive. We have shown that, after a long latency, human-Cathepsin G-(hCG) PML-RARa transgenic mice (TM) develop RA-sensitive APL like leukemia, while hCG-PLZF-RARa TM develop myeloid leukemia which lacks the promyelocytic block and are RA resistant. To dissect in vivo the mechanisms underlying leukemogenesis, we have generated and characterized hCG-RARaE (5 lines), hCGRARaM4 (4 lines), hCG-PML-RARaM4 (6 lines) and hCG-ARARa (4 lines) TM. RARaM4 and PML-RARaM4 harbor the same point mutation in the ligand-binding domain, which impairs their ability to bind RA and to activate transcription. RARaE harbors a different point mutation in its RA-binding domain, which renders it a potent transcriptional repressor unresponsive to RA, thus mimicking the X-RARa oncoproteins. ARARa is missing the RARa transactivation domain A, which in all the X-RARa proteins is replaced by the X moiety. PML-RARaM4 TM developed full-blown RAresistant APL like leukemia. Strikingly, RARaE TM also developed leukemia, similarly after a long latency (PML-RARaM415 months; RARaE 18 months). By contrast, RARaM4 and ARARa TM did not develop leukemia. These data suggest in vivo that transcriptional repression of the RARo/RXR pathway is necessary, albeit not sufficient, for leukemogenesis. The inactivation of the X pathway(s) by X-RARa and the concomitant activity of the RARa-X fusion protein may cooperate to full-blown APL.

Original languageEnglish (US)
Pages (from-to)91a
JournalBlood
Volume96
Issue number11 PART I
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Bhaumik, M., Changou, A. C., Rego, E. M., Zelent, A., Miller, W., & Pandolfi, P. P. (2000). Transcriptional repression of the rara pathyway is crucial for leukemogenesis. Blood, 96(11 PART I), 91a.