P210 and P190 Induce the Tyrosine Phosphorylation and DNA Binding Activity of Multiple Specific STAT Family Members

Abstract

The products of the Philadelphia chromosome translocation, P210 and P190 BCR/ABL , are cytoplasmic protein tyrosine kinases that share the ability to transform hematopoietic cytokine-dependent cell lines to cytokine independence but differ in the spectrum of leukemia induced in vivo. We have analyzed the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways in hematopoietic cells transformed by Bcr/Abl. STAT5 and, to a lesser extent, STATs 1 and 3 were constitutively activated by tyrosine phosphorylation and induction of DNA binding activity in both P210 and P190 BCR/ABL-transformed cells, but P190 differed in that it also prominently activated STAT6. There was low level tyrosine phosphorylation of JAKs 1, 2, and 3 in Bcr/Abl-transformed cells, but no detectable complex formation with Bcr/Abl, and activation of STAT5 by P210 was not blocked by two different dominant-negative JAK mutants. These results suggest that P210 and P190 BCR/ABL directly activate specific STAT family members and may help explain their overlapping yet distinct roles in leukemogenesis.

STAT signaling in the pathogenesis and treatment of leukemias

“…Additionally, Jak kinase activity was not consistently observed, suggesting direct tyrosine phosphorylation and activation of STAT1 and STAT5 by Bcr/Abl. Similar studies by Ilaria and Van Etten (1996) using the same expression plasmid and Ba/F3 and FDC-P1 cell lines revealed primarily tyrosine phosphorylation and activation of STAT5, although less prominent STAT1 and STAT3 activation was also seen. The Bcr/ Abl-positive CML lines K562, KBM5 and EM2 all demonstrated constitutive STAT5 tyrosine phosphorylation, whereas no such activation was seen in the Bcr/Abl-negative leukemia cell lines HL-60, U937 and BJAB.…”

“…Ilaria and Van Etten (1996) noted that, in contrast to the STAT5 activation induced by p210 in Ba/F3 and FDC-P1 transfectants, transfection and expression of the p190 form of Bcr/ Abl induced tyrosine phosphorylation and activation of STAT6. This is intriguing, given that IL-4, a major cytokine regulating lymphocyte function, is known to activate this STAT member.…”

The biology of Stat4 and Stat6

“…There are a few examples of constitutive Stat6 activation in transformed cell lines. For example, one of the products of the Philadelphia chromosome translocation, p190 BCR/ABL , is capable of inducing prominent Stat6 activation in the absence of cytokine (Ilaria and Van Etten, 1996). Additionally, HTLV-1 transformed T cells also constitutively activate the JAK/Stat6 pathway (Takemoto et al, 1997).…”

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…Transformation by tyrosine kinase fusion genes associated with human leukemia has been persistently linked to activation of Stat5. For instance, BCR/ABL expression due to Philadelphia chromosome translocation leads to Stat1 and Stat5 activation in chronic myelogenous leukemia (Carlesso et al, 1996;Chai et al, 1997;Ilaria and Van Etten, 1996;Shuai et al, 1996), and fusion of the JAK2 protein to the ets protein TEL causes Stat activation and myeloproliferative disease Lacronique et al, 1997;Schwaller et al, 1998). Stat5 is also activated by the TEL/PDGFbR, TEL/ABL and HIP1/PDGFbR oncogenic fusion proteins (Okuda et al, 1996;Ross and Gilliland, 1999;Sternberg et al, 1999).…”