By Pier Paolo Pandolfi (Editor), Peter K. Vogt (Editor)
During the last 10 years, paintings on acute promyelocytic leukemia (APL) has turn into the paradigm of translational examine that begun with the invention of a recurrent chromosomal translocation, by means of the id of the genes and proteins concerned, discovering their molecular services in transcriptional keep an eye on, setting up mouse versions and culminating within the improvement of exact remedy.
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Additional resources for Acute Promyelocytic Leukemia: Molecular Genetics, Mouse Models and Targeted Therapy (Current Topics in Microbiology and Immunology 313)
The modiﬁcation occurred at a lysine in RD2, the second repression domain of PLZF . Sumoylation increased DNA binding, and mutation of this lysine residue (K242) resulted in decreased DNA binding and transcriptional repression, suggesting that sumoylation augments transcriptional repression by PLZF. Whether PLZF sumoylation occurs in vivo has not been determined, although PLZF is found in PML bodies, where a number of proteins are known to be sumoylated. Further, sumoylation is associated with transcriptional repression and repressive chromatin, again reminiscent of the action of PLZF .
The effect of SU11657 on leukemias that arose in cells expressing MRP8 PML-RARA plus an activated FLT3 was assessed (Sohal et al. 2003). Although SU11657 had limited effect as a single agent, the combination of SU11657 plus ATRA rapidly restored normal hematopoiesis in the bone marrow and resulted in a marked reduction in splenic involvement by the leukemic cells. A number of FLT3 inhibitors are under study in human clinical trials (Krause and Van Etten 2005). Cyclic adenosine monophosphate (cAMP) has growth suppressive and differentiative effects on myeloid leukemia cells.
Proc Natl Acad Sci U S A 99:8283–8288 Mouse Models of Acute Promyelocytic Leukemia 27 Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K, Takeshita A, Saito K, Hasegawa S, Shimodaira S, Tamura J, Shimazaki C, Matsue K, Kobayashi H, Arima N, Suzuki R, Morishita H, Saito H, Ueda R, Ohno R (1997) Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia 11:1447–1452 Kogan SC, Hong SH, Shultz DB, Privalsky ML, Bishop JM (2000) Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable.