Regulative Loop between β-catenin and Protein Tyrosine Receptor Type γ in Chronic Myeloid Leukemia

Abstract

Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene, down-regulated in Chronic Myeloid Leukemia (CML) cells by the hypermethylation of its promoter region. β-catenin (CTNNB1) is a critical regulator of Leukemic Stem Cells (LSC) maintenance and CML proliferation. This study aims to demonstrate the antagonistic regulation between β-catenin and PTPRG in CML cells. The specific inhibition of PTPRG increases the activation state of BCR-ABL1 and modulates the expression of the BCR-ABL1- downstream gene β-Catenin. PTPRG was found to be capable of dephosphorylating β-catenin, eventually causing its cytosolic destabilization and degradation in cells expressing PTPRG. Furthermore, we demonstrated that the increased expression of β-catenin in PTPRG-negative CML cell lines correlates with DNA (cytosine-5)-methyl transferase 1 (DNMT1) over-expression, which is responsible for PTPRG promoter hypermethylation, while its inhibition or down-regulation correlates with PTPRG re-expression. We finally confirmed the role of PTPRG in regulating BCR-ABL1 and β-catenin phosphorylation in primary human CML samples. We describe here, for the first time, the existence of a regulative loop occurring between PTPRG and β-catenin, whose reciprocal imbalance affects the proliferation kinetics of CML cells.

Chronic Myeloid Leukemia Preceded by Tuberculosis

“…Exposure to ionizing radiation is the only known risk factor for CML [4]. Tyrosine kinase inhibitors are a cornerstone in the management of CML around the world with good results [5][6][7][8][9]. This case is shedding light on a possible association between TB and the development of CML.…”

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

“…Consistently, over-expression of LEF-1 mRNA is a hallmark in ALL and CLL patients with poor prognostic. The constitutive activation of the pathway deregulation can result from gene mutation ( Tomasello et al, 2020 ), but also from epigenetic modifications. In CLL for example, Next generation sequencing of samples from patients confirmed that 40% of patients harbors somatic mutations in Wnt pathway components ( WNT1 , WNT10A , DKK2 , RSPO4, FZD5, RYK ) ( Wang et al, 2014 ).…”

“…Concerning myeloid malignancies, Zhao et al found that β-catenin deletion causes a reduction in the ability of mice to develop BCR-ABL-induced CML ( Zhao et al, 2007 ). Indeed, stabilization and nuclear localization of β-catenin is a direct consequence of the BCR-ABL ( Tomasello et al, 2020 ). As a consequence, the treatment of CML stem/progenitor cells with β-catenin inhibitor ICG001 reduces cell survival and proliferation by sensitizing cells to tyrosine kinase inhibitors (TKI).…”

“…-MSC-induced accumulation of β-catenin in CLL cells, supports drug resistance of leukemia cells (Mangolini et al, 2018). Oncogene -β-catenin is a target of BCR-ABL (Zhao et al, 2007;Tomasello et al, 2020) -Wnt1 signaling supports growth and survival of CML cells (Majeti et al, 2009).…”

Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

“…This limitation of BCR-ABL1 prevents complete β-catenin phosphorylation, with consequent destabilization and proteasome degradation. In addition, PTPRG seems to directly dephosphorylate β-catenin, providing further details on its tumor-suppressive effects in CML [ 118 ]. Methylation play an extremely important role in the regulation of PTPRG expression in CML—a feature shared with other malignancies [ 119 ].…”