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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1541-1550
PLENARY PAPER
Leukemia initiated by PMLRAR : the PML domain plays a
critical role while retinoic acid-mediated transactivation is
dispensable
Scott C. Kogan,
Suk-hyun Hong,
David B. Shultz,
Martin L. Privalsky, and
J. Michael Bishop
From the G.W. Hooper Foundation and Departments of Laboratory
Medicine and Microbiology & Immunology, University of California, San
Francisco, CA; and the Section of Microbiology, Division of Biological
Sciences, University of California, Davis, CA.
The most common chromosomal translocation in acute promyelocytic
leukemia (APL), t15;17(q22;q21), creates PMLRAR and
RARPML fusion genes. We previously developed a mouse model
of APL by expressing PMLRAR in murine myeloid cells. In
order to examine the mechanisms by which PMLRAR can initiate
leukemia, we have now generated transgenic mice expressing
PMLRARm4 and RARm4, proteins that are unable to
activate transcription in response to retinoic acid.
PMLRARm4 transgenic mice developed myeloid leukemia,
demonstrating that transcriptional activation by PMLRAR is
not required for leukemic transformation. The characteristics of the
leukemias arising in the PMLRARm4 transgenic mice varied from those previously observed in our PMLRAR transgenic
mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARm4
transgenic mice did not differentiate in response to retinoic acid
therapy. This result supports the hypothesis that a major therapeutic
effect of retinoic acid is mediated directly through the
PMLRAR protein. However, a variable effect on survival
suggested that this agent may be of some benefit in APL even when
leukemic cells are resistant to its differentiative effects.
Transgenic mice expressing high levels of RARm4 have
not developed leukemia, providing evidence that the PML domain of
PMLRAR plays a specific and critical role in the
pathogenesis of APL.
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