ANP32A dysregulation contributes to abnormal megakaryopoiesis in acute megakaryoblastic leukemia

Sun, Xueqin; Lü, Bin; Han, Cuijuan; Qiu, Wanlin; Qi, Jin; Li, Dengju; Li, Qiubai; Yang, Qiong; Wen, Qiang; Opal, Puneet; Kini, Ameet R.; Crispino, John D.; Huang, Zan

doi:10.1038/s41408-017-0031-x

Cited by 12 publications

(18 citation statements)

References 9 publications

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“…Binds and inhibits B55αδ in mitosis [98,99] ARPP19 promotes MYC expression [100] High expression [100] ANP32A, (acidic nuclear phosphoprotein 32a), also known as I1PP2A (Inhibitor 1 of PP2A), is a potent inhibitor of PP2A catalytic subunit [87,88]. It is overexpressed in primary AML cells [89] and is a critical factor that contributes to acute megakaryoblastic leukemia progression [101].…”

Section: Arpp19mentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

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Section: Arpp19mentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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“…ANP32A, also referred to as I1PP2A, acts as a tumour suppressor and ANP32C is oncogenic, with both aberrantly expressed in human malignancy [64, 65]. Their involvement has been reported in colorectal cancer [71], oral cancers [72], leukaemia [73], and prostate cancer [74], but neither have been reported to be pivotal in lung carcinogenesis.…”

Section: Mechanisms Responsible For Pp2a Inactivationmentioning

confidence: 99%

“…Whilst insufficient research addresses the role of SET in COPD, SET has been explored extensively in cancerous tissue. SET is a well-established oncogene in a number of different human malignancies [73, 108–111]. LC is no exception, with SET identified to be overexpressed in NSCLC, adenocarcinoma and LC cell lines [34, 35, 112].…”

Section: Mechanisms Responsible For Pp2a Inactivationmentioning

confidence: 99%

Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer

et al. 2019

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Lung cancer (LC) has the highest relative risk of development as a comorbidity of chronic obstructive pulmonary disease (COPD). The molecular mechanisms that mediate chronic inflammation and lung function impairment in COPD have been identified in LC. This suggests the two diseases are more linked than once thought. Emerging data in relation to a key phosphatase, protein phosphatase 2A (PP2A), and its regulatory role in inflammatory and tumour suppression in both disease settings suggests that it may be critical in the progression of COPD to LC. In this review, we uncover the importance of the functional and active PP2A holoenzyme in the context of both diseases. We describe PP2A inactivation via direct and indirect means and explore the actions of two key PP2A endogenous inhibitors, cancerous inhibitor of PP2A (CIP2A) and inhibitor 2 of PP2A (SET), and the role they play in COPD and LC. We explain how dysregulation of PP2A in COPD creates a favourable inflammatory micro-environment and promotes the initiation and progression of tumour pathogenesis. Finally, we highlight PP2A as a druggable target in the treatment of COPD and LC and demonstrate the potential of PP2A re-activation as a strategy to halt COPD disease progression to LC. Although further studies are required to elucidate if PP2A activity in COPD is a causal link for LC progression, studies focused on the potential of PP2A reactivating agents to reduce the risk of LC formation in COPD patients will be pivotal in improving clinical outcomes for both COPD and LC patients in the future.

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“…Based on the features of the AMKL patients, leukaemic blasts exhibit inde nite proliferation and fail to undergo differentiation or polyploidization, and recent research has proposed that forcing immature AMKL cells to undergo differentiation is a good therapeutic strategy (Nurhayati et al 2015;Wen et al 2012). AURKA inhibitors (diMF or MLN8237) have effectively induced the differentiation of 6133/MPL and CMK megakaryocytes, and prolonged the survival of 6133/MPL transplanted mice (Wen et al 2012); tetrandrine antagonizes AMKL cell growth by forcing autophagy-mediated differentiation (Liu et al 2017); knockdown of ANP32A also effectively prolonged the survival of transplanted mice by promoting the differentiation of 6133/MPL megakaryocytes (Sun et al 2017). The latest report shows that HDAC inhibitors promoted MEG-01 cells transition to megakaryocytes (MKs) and platelet-like particles, indicating a potential and available strategy in AMKL therapy (Dhenge et al 2019).…”

Section: Introductionmentioning

confidence: 99%

PAK1 Inhibition Slows Growth and Partially Promotes Differentiation of AMKL Cells

wang

et al. 2021

Preprint

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Purpose Acute megakaryoblastic leukaemia is characterized by the expansion of megakaryoblasts, which are hyperproliferative and fail to undergo differentiation or polyploidization. Although recent studies have proposed that inducing immature AMKL cells to undergo differentiation is a good therapeutic strategy, there is still no satisfactory medicine for clinical application because of the unclear enrichment of megakaryoblasts. It has been reported that p21 (RAC1)-activated kinase 1 (PAK1) participates in megakaryoblastic proliferation and differentiation, and its upregulation is related to AML development, but its role in AMKL remains unclear. Method The mRNA level of PAK1 was analyzed according the GSE4119 dataset by calculating the copy numbers of PAK1 to GAPDH. The protein level of PAK1 was detected in primary mouse AMKL cells with overexpression of MPLW515L mutant gene. The biological function was examined in AMKL cells after PAK1 inhibition by EdU staining, western blot, Annexin V/FITC, and ﬂow cytometry assay, respectively.Results Here, we found that the mRNA and protein level of PAK1 was enriched in AMKL patients or cells, and inhibition of PAK1 significantly induced the arrested growth of the AMKL cell line. Further analysis of the protein expression of downstream of PAK1 showed that blocking the activity of PAK1 downregulated the expression of cyclin D1. Two PAK1 inhibitors partially and modestly promoted polyploidy formation in both CHRF and CMK cells. Additionally, these PAK inhibitors consistently promoted cell apoptosis by upregulating cleaved caspase 3. In accordance with the inhibitor effects on AMKL cells, PAK1 knockdown also increased the polyploid DNA content of CHRF and CMK cells and significantly induced cell apoptosis. Conclusions These results suggest that PAK1 might be a critical gene that drives the proliferation and differentiation of AMKL cells, and inhibiting the activity of PAK1 might be an effective method of controlling AMKL.

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ANP32A dysregulation contributes to abnormal megakaryopoiesis in acute megakaryoblastic leukemia

Cited by 12 publications

References 9 publications

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer

PAK1 Inhibition Slows Growth and Partially Promotes Differentiation of AMKL Cells

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ANP32A dysregulation contributes to abnormal megakaryopoiesis in acute megakaryoblastic leukemia

Cited by 12 publications

References 9 publications

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer

PAK1&nbsp;Inhibition Slows Growth and Partially Promotes Differentiation of AMKL&nbsp;Cells

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PAK1 Inhibition Slows Growth and Partially Promotes Differentiation of AMKL Cells