The Cell Polarity and Scaffolding Protein, PAR3, Acts as A Tumour Suppressor in Acute Myeloid Leukemia Through Regulation of the Hippo Pathway

Abstract The pseudo tyrosine kinase receptor 7 (PTK7) is an orphan tyrosine kinase receptor assigned to the planar cell polarity pathway. It plays a major role during embryogenesis and epithelial tissue organization. Here we found that PTK7 is also expressed in normal myeloid progenitors and CD34+ CD38− bone marrow cells in humans. We performed an immunophenotyping screen on more than 300 patients treated for hematologic malignancies. We demonstrated that PTK7 is expressed in acute myeloid leukemia (AML) and is mostly assigned to granulocytic lineage differentiation. Patients with PTK7-positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced leukemia-free survival in a multivariate analysis model. In vitro, expression of PTK7 in cultured leukemia cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis. The intracellular region of PTK7 is required for these effects. Furthermore, we efficiently sensitized primary AML blasts to anthracycline-mediated cell death using a recombinant soluble PTK7-Fc protein. We conclude that PTK7 is a planar cell polarity component expressed in the myeloid progenitor compartment that conveys promigratory and antiapoptotic signals into the cell and that represents an independent prognosis factor of survival in patients treated with induction chemotherapy.

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Identification of a fusion gene composed of a Hippo pathway gene MST2 and a common translocation partner ETV6 in a recurrent translocation t(8;12)(q22;p13) in acute myeloid leukemia

Annals of Hematology ◽

10.1007/s00277-015-2391-2 ◽

2015 ◽

Vol 94 (8) ◽

pp. 1431-1433 ◽

Cited By ~ 4

Author(s):

Shinichi Ogawa ◽

Yasuhisa Yokoyama ◽

Kazumi Suzukawa ◽

Toru Nanmoku ◽

Naoki Kurita ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Hippo Pathway ◽

Pathway Gene ◽

Recurrent Translocation ◽

Acute Myeloid

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PRICKLE1, a Wnt/PCP signaling component, is overexpressed and associated with inferior prognosis in acute myeloid leukemia

Journal of Translational Medicine ◽

10.1186/s12967-021-02873-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Duanfeng Jiang ◽

Yanjuan He ◽

Qiuyu Mo ◽

Enyi Liu ◽

Xin Li ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Polarity ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Planar Cell Polarity ◽

Expression Profiles ◽

Prognostic Significance ◽

Migration And Invasion ◽

Canonical Wnt ◽

Acute Myeloid

Abstract Background Prickle planar cell polarity protein 1 (PRICKLE1), a core component of the non-canonical Wnt/planar cell polarity (PCP) pathway, was recently reported to be upregulated and correlated with poor prognosis in solid cancers. However, the effect of PRICKLE1 on acute myeloid leukemia (AML) remains unknown. This study aims to characterize the prognostic significance of PRICKLE1 expression in patients with AML. Methods RNA-seq was performed to compare mRNA expression profiles of AML patients and healthy controls. qRT-PCR and western blotting were used to analyze the expression of PRICKLE1 in AML patients and cell lines, and two independent datasets (TCGA-LAML and TARGET-AML) online were used to validate the expression results. The correlations between the expression of PRICKLE1 and clinical features were further analyzed. Results Our data showed that PRICKLE1 expression levels were markedly high in AML patients at the time of diagnosis, decreased after complete remission and increased again at relapse. Of note, PRICKLE1 was highly expressed in drug resistant AML cells and monocytic-AML patients. High PRICKLE1 expression was found in FLT3/DNMT3A/IDH1/IDH2-mutant AML and associated with poor prognosis. Furthermore, high expression of PRICKLE1 may be correlated with migration and invasion components upregulation in AML patients. Conclusions These results indicated that high PRICKLE1 expression may be a poor prognostic biomarker and therapeutic target of AML.

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