Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy with poor prognosis. 1 Core-binding factor AML is cytogenetically defined by the presence of t (8; 21)(q22; q22) or inv (16)(p13q22)/t (16; 16)(p13; q22), commonly abbreviated as t (8; 21) and inv (16), respectively. 2, 3 In both subtypes, the cytogenetic rearrangements disrupt genes that encode subunits of core-binding factor, a transcription factor that functions as an essential regulator of normal hematopoiesis. 2, 3 The t (8; 21) translocation, which generates the AML1-ETO fusion gene, is one of the most common chromosomal abnormalities detected in AML. 4 The AML1-ETO fusion transcription factor is present in~ 4–12% of adult and 12–30% of pediatric AML patients. 4 AML1-ETO+ AML remains a significant clinical problem, with 30% of patients relapsing and long‐term survival rates ranging between 30 and 60%, indicating the need for improved therapeutic approaches. 2–4 The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL1, PRL2 and PRL3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in human cancer. 5 Notably, recent findings indicate that PRLs may have important roles in the pathogenesis of hematological malignancies. 6 Both PRL2 and PRL3 are highly expressed in some hematological malignancies, including AML, CML, multiple myeloma and acute lymphoblastic leukemia (ALL). 6 High PRL3 mRNA expression is associated with FLT3-ITD mutations and poor prognosis in AML patients with normal karyotype. 7 We have identified PRL2 to be important for the proliferation and selfrenewal of hematopoietic stem cells through the regulation of KIT signaling. 8 Recently, we found that PRL2 mediates NOTCH and KIT signals in early T-cell progenitors and that PRL2 is essential for oncogenic NOTCH1-induced T-cell leukemia in vivo. 9, 10 An improved understanding of how PRLs function and how they are regulated may establish PRLs as novel therapeutic targets in AML.

PRL2 is highly expressed in some subtypes of AML, including AML1-ETO+ AML and AML with mixed lineage leukemia translocations (Figure 1a). The PRL2 expression profiling data were obtained from the HemaExplorer, a Web server for easy and fast visualization of gene expression in normal and malignant hematopoiesis. 11 We observed that the levels of PRL2 protein were elevated in several human AML cell lines compared with cord blood and peripheral blood mononuclear cells from healthy donors (Supplementary Figure S1a). However, the role of PRL2 in the proliferation and survival of human AML cells is largely unknown. Kasumi-1 is a human AML cell line with AML1-ETO and MV4-11 is a human B-myelomonocytic leukemia cell line with mixed lineage leukemia translocation. We found that knockdown of PRL2 decreased the proliferation of both Kasumi-1 and MV4-11 cells (Figures 1b and c and Supplementary Figure S1b). We also found that ectopic expression of a PRL2 dominant-negative mutant PRL2/C101S-D69A (PRL2/CS-DA) reduced the proliferation of Kasumi-1 cells (Supplementary Figure S1c). Recently, we identified a small-molecule PRL inhibitor (PRLi) using computer-based virtual screening. 12 Intraperitoneally injection of 15 mg/kg of PRLi into wild-type mice daily for 3 weeks exhibited no toxicity and body weight and weights of major organs (liver, spleen and kidney) were comparable to dimethyl sulfoxide-treated mice. 12 PRLi did not affect the viability of human cord blood mononuclear cells and CD34+ cells. 10 Further, we found that pharmacological inhibition of PRL2 …