The Pro-Metastasis Tyrosine Phosphatase, PRL-3 (PTP4A3), Is a Novel Target of BCR-ABL Signaling Involved in Human Chronic Myeloid Leukemia

Abstract 2741

Chronic myeloid leukemia (CML) is the best and most successful disease model for tyrosine kinase inhibitor (TKI). The mechanism of BCR-ABL leading transformation and signaling transduction networks have been intensively characterized over decades. However, resistance to TKIs remains a challenge in management of patients with CML. A better understanding BCR-ABL signaling network will lead to a better therapy.

Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 (PTP4A3), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. A search of Gene Expression Atlas (http://www.ebi.ac.uk/gxa/gene/ENSG00000184489) identified the expression level of PRL-3 was highest in CML among 950 human cancer cell lines crossing 32 different types of cancers (Dataset code: E-MTAB-37), suggesting a potential role of PRL-3 in CML pathogenesis. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BRC-ABL in CML cell line K562, KCL-22 and primary patient samples reduces PRL-3, in parallel with suppression of signal transducer and activator of transcription (STAT) pathway activities and increased cleavage of PARP, a hallmark of apoptosis. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing BaF3-P210 T315I. Finally, analysis with specific shRNA demonstrated K562-shPRL-3 (shP) cells proliferated as much as 2-time lesser than K562-shControl (shC) at day 8 (p < 0.001). Colony-forming efficiency is an indicator of self-renewal capacity of leukemic cell. K562-shP cells also showed significantly impaired colony generating capacity by 3-fold compared to K562-shC (p < 0.001). These results indicate a critical role for PRL-3 in CML cell expansion and self-renewal.

In summary, the present study demonstrates that PRL-3 is remarkably upregulated in human CML cell lines, BCR-ABL transformed cell lines and primary CML patient samples. Our results highlight that PRL-3 is a novel downstream target of BCR-ABL pathway, which is crucial for BRC-ABL-mediated cell survival and self-renewal. These data support a functionally important role of PRL-3 in CML biology downstream of BCR-ABL and maybe a viable therapeutic target in BCR-ABL positive cells even in those with Imatinib resistant mutations.