The JAK-STAT pathway is an important physiologic regulator of different cellular functions including
proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins,
STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seems to be a key event in the
pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable
of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have
shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with
JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical
trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical
trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds
could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors
in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic
stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the
cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review, we discuss the
implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.
Keywords: STAT transcription factors, STAT5 inhibitors, leukemia, BCR-ABL, FLT3-ITD, Jak2V617F.
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