Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia

Kobayashi, Michihiro; Chen, S.; Bai, Yunpeng; Yao, Chonghua; Gao, Rui; Sun, Xiao Jian; Mu, Chaofeng; Twiggs, Taylor A.; Yu, Zhi; Boswell, H. Scott; Yoder, Mervin C.; Kapur, Reuben; Mulloy, James C.; Zhang, Z. Y.; Liu, Y.

doi:10.1038/leu.2017.67

Cited by 9 publications

(9 citation statements)

References 16 publications

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“…A series of studies by Kobayashi et al . confirmed the oncogenic function of PRL‐2 in both Notch1‐induced and AML1‐ETO‐induced T cell leukemias . PRL‐2 KO resulted in changes in cell viability and proliferation in vitro and impacted cancer growth and survival in vivo .…”

Section: Prls In Hematological Malignancymentioning

confidence: 56%

“…As in other physiological systems, the above-mentioned studies demonstrate that manipulating PRL-2 expression in immune cells also results in changes that could impact malignant potential of cancer cells. A series of studies by Kobayashi et al confirmed the oncogenic function of PRL-2 in both Notch1-induced and AML1-ETOinduced T cell leukemias [40,129]. PRL-2 KO resulted in changes in cell viability and proliferation in vitro and impacted cancer growth and survival in vivo [40,129].…”

Section: Prl-2 In T Cells and Leukemiamentioning

confidence: 97%

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Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL-1, -2, -3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport.

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Section: Prls In Hematological Malignancymentioning

confidence: 56%

Section: Prl-2 In T Cells and Leukemiamentioning

confidence: 97%

Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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“…While AML1-ETO is insufficient to cause acute leukemia by itself in human or mouse cells [ 14 – 15 ], AML1-ETO9a fusion protein is sufficient to cause leukemia in mice [ 16 – 17 ]. To determine the role of Necdin in AML1-ETO9a-induced leukemia, we introduced AML1-ETO9a into wild type and Necdin null fetal livers cells and performed transplantation assays.…”

Section: Discussionmentioning

confidence: 99%

“…Retroviral particles were produced by transfection of Phoenix E cells with the MSCV-MLL-AF9- IRES-GFP or MSCV-AML1-ETO9a-IRES-GFP plasmids, according to standard protocols [ 17 ]. Murine fetal liver cells were transduced on retronectin (Takara)-coated non-tissue culture plates with high-titer retroviral suspensions.…”

Section: Methodsmentioning

confidence: 99%

“…AML1-ETO is insufficient to cause acute leukemia by itself in human or mouse cells [ 14 – 15 ]. However, a truncated form of the AML1-ETO fusion protein (called AML1-ETO exon 9a) is sufficient to cause leukemia in mice, with a rather short latency [ 16 – 17 ]. 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 [ 18 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Necdin modulates leukemia-initiating cell quiescence and chemotherapy response

et al. 2017

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Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.

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