Abstract
Loss of PTEN, a negative regulator of the phosphoinositide 3-kinase signaling pathway, is a frequent event in T-cell acute lymphoblastic leukemia, suggesting the importance of phosphoinositide 3-kinase activity in this disease. Indeed, hyperactivation of the phosphoinositide 3-kinase pathway is associated with the disease aggressiveness, poor prognosis and resistance to current therapies. To identify a molecular pathway capable of cooperating with PTEN deficiency to drive oncogenic transformation of leukocytes, we performed an unbiased transformation screen with a library of tyrosine kinases. We found that activation of NTRK2 is able to confer a full growth phenotype of Ba/F3 cells in an IL3-independent manner in the PTEN-null setting. NTRK2 activation cooperates with PTEN deficiency through engaging both phosphoinositide3-kinase/AKT and JAK/STAT3 pathway activation in leukocytes. Notably, pharmacological inhibition demonstrated that p110α and p110δ are the major isoforms mediating the phosphoinositide 3-kinase/AKT signaling driven by NTRK2 activation in PTEN-deficient leukemia cells. Furthermore, combined inhibition of phosphoinositide 3-kinase and STAT3 significantly suppressed proliferation of PTEN-mutant T-cell acute lymphoblastic leukemia both in culture and in mouse xenografts. Together, our data suggest that a unique conjunction of PTEN deficiency and NTRK2 activation in T-cell acute lymphoblastic leukemia, and combined pharmacologic inhibition of phosphoinositide 3-kinase and STAT3 signaling may serve as an effective and durable therapeutic strategy for T-cell acute lymphoblastic leukemia.
Highlights
The class-I phosphoinositide 3-kinase (PI3K) signaling cascade is a central pathway activated in many cancers, including hematological malignancies [1]
Upon short-term treatments of Ba/F3 ShPTEN-Neurotrophic Tyrosine Receptor Kinase Type 2 (NTRK2)-Tel as well as T-cell acute lymphoblastic leukemia (T-ALL) cell lines with PI3K isoform-selective inhibitors, we found that BYL719 [18] greatly reduced AKT but not S6 phosphorylation, whereas GS-1101 [19] inhibited S6 protein phosphorylation or AKT phosphorylation depending on cell lines (Figure 4a and b)
We report that NTRK2, a kinase that emerged from an unbiased activated receptor tyrosine kinase (RTK) screen, may be a potential therapeutic target in a subset of T-ALL with PTEN deficiency
Summary
The class-I phosphoinositide 3-kinase (PI3K) signaling cascade is a central pathway activated in many cancers, including hematological malignancies [1]. Activation of the pathway begins when a receptor tyrosine kinase (RTK) at cell surface is activated, resulting in recruitment of PI3K to the plasma membrane where it phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to form phosphatidylinositol (3,4,5)-triphosphate (PIP3). This lipid product of PI3Ks acts as a second messenger to trigger diverse signaling cascades that promote cell survival, proliferation and differentiation. Loss of PTEN leads to a constitutively hyperactivated PI3K pathway, an event frequently found in human cancer, including hematological malignancies. Anywhere between 8 and 63% of T-cell acute lymphoblastic leukemia (T-ALL) patients have mutated or lost PTEN tumor suppressor gene [2,3,4,5], suggesting the importance of the PI3K pathway in T-cell leukemia and providing the rationale for the development of PI3K-targeted therapies in T-ALL
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