Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms

Ueda, Koki; Ikeda, Kazuhiko; Ikezoe, Takayuki; Harada-Shirado, Kayo; Ogawa, Kaoru; Hashimoto, Yuko; Sano, Tsuyoshi; Ohkawara, Hiroshi; Kimura, Satoshi; Shichishima-Nakamura, Akiko; Nakamura, Yūichi; Shikama, Yayoi; Mori, T.; Mason, Philip J.; Morishita, Soji; Komatsu, Norio; Shide, Kotaro; Shimoda, Kazuya; Koide, Shuhei; Aoyama, Kazumasa; Oshima, Motohiko; Iwama, Atsushi; Takeishi, Yasuchika

doi:10.1182/bloodadvances.2017004457

Cited by 17 publications

(28 citation statements)

References 64 publications

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“…For example, ANRIL could not only interact with SUZ12 (a subunit of the PRC2) and recruit the complex to inhibit the expression of p15 (INK4B), a well-known tumor suppressor gene [8,43,44], but also work in concert with other epigenetic regulators, such as p300 (a histone acetylator), and EZH2 (a histone methyltransferase component of the PRC2 complex) [45,46]. More importantly, previous studies have found that the oncogene HMGA2 may be one of the most important targets up-regulated by the mutations of PRC2 components and encourages the development of HMGA2-targeted therapy for patients with cancers [47,48]. The above evidence suggested that silencing ANRIL could promote ovarian cancer cell apoptosis, increase cisplatin-induced cell apoptosis and improve cisplatin-sensitivity by binding with PRC2 complexes to inhibit HMGA2.…”

Section: Discussionmentioning

confidence: 99%

LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis

et al. 2019

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This paper tried to explore ANRIL expression in ovarian cancer and how it affects cisplatin-sensitivity of ovarian cancer cells via regulation of let-7a/high-mobility group protein A2 (HMGA2) axis. qRT-PCR was used to detect ANRIL and let-7a levels in ovarian cancer tissues and cell lines (SKOV3 and SKOV3/DDP). Then cells were randomly assigned into Blank, negative control siRNA, ANRIL siRNA, let-7a inhibitor, and ANRIL siRNA+let-7a-inhibitor groups. CCK-8 assay was applied for assessing cell viability of cells treated with different concentrations of cisplatin. Flow cytometry was employed to test cell apoptosis rate. qRT-PCR and Western blot were performed for related molecules detection. Nude mice transplanted with SKOV3/DDP cells were used to confirm the effects of ANRIL siRNA on the cisplatin-sensitivity. Ovarian cancer tissues and cisplatin-resistant cells had increased ANRIL expression and decreased let-7a expression, and those patients with higher clinical stage and pathological grade showed higher ANRIL and lower let-7a. Dual-luciferase reporter-gene assay confirmed the targeting relationship between ANRIL and let-7a, and between let-7a and HMGA2. The cell viability and cisplatin IC50 were decreased in ANRIL siRNA group exposed to different concentrations of cisplatin, with enhanced apoptosis, as well as elevated let-7a and declined HMGA2, which would be reversed by let-7a inhibitor. Meanwhile, ANRIL down-regulation enhanced the inhibitory effect of cisplatin on tumor growth of nude mice and reduced tumor weight. Silencing ANRIL expression reduced HMGA2 expression to promote the apoptosis and improve cisplatin-sensitivity of ovarian cancer cells via up-regulating let-7a expression.

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Section: Discussionmentioning

confidence: 99%

LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis

et al. 2019

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“…We enrolled 39 patients with JAK2 V617F-positive MPN whose computed tomography data were available in a series of our former studies. 18 , 19 We evaluated the maximal diameter of the ascending aorta and abdominal aorta via computed tomography imaging. The protocol of the human studies was approved by the Institutional Ethics Committee of the Fukushima Medical University Hospital (approval ID, 29348 and 1242).…”

Section: Methodsmentioning

confidence: 99%

“…We used male Jak2 V617F-expressing transgenic (JAK2 V617F ) mice. 7 , 19 Wild-type (WT) littermates were used as controls. Male apolipoprotein E-deficient (ApoE −/− ) mice on a C57BL/6J background were obtained from the Jackson Laboratory (JAX stock number, 002052, Bar Harbor, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

Crucial role of hematopoietic <i>JAK2</i> V617F in the development of aortic aneurysms

et al. 2021

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JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.

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“…To elucidate the roles of hematopoietic Calr mutation in PH, we performed non-competitive BMT from Calr del10/WT mice (Fig. 1 c), as we reconstituted Jak2 V617F + MPNs [ 11 ]. At 4 weeks after BMT, the engraftments were achieved in the BMT recipients from Calr del10/WT mice (del-R, Fig.…”

Section: To the Editormentioning

confidence: 99%

Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice

et al. 2021

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Frameshifts in the Calreticulin (CALR) exon 9 provide a recurrent driver mutation of essential thrombocythemia (ET) and primary myelofibrosis among myeloproliferative neoplasms (MPNs). Here, we generated knock-in mice with murine Calr exon 9 mimicking the human CALR mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [Calrdel10/WT (wild−type) mice] exhibited an ET phenotype with increases of peripheral blood (PB) platelets and leukocytes, and accumulation of megakaryocytes in bone marrow (BM), while those with ins2 (Calrins2/WT mice) showed a slight splenic enlargement. Phosphorylated STAT3 (pSTAT3) was upregulated in BM cells of both knock-in mice. In BM transplantation (BMT) recipients from Calrdel10/WT mice, although PB cell counts were not different from those in BMT recipients from CalrWT/WT mice, Calrdel10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calrdel10/WT mice developed more severe pulmonary hypertension (PH)—which often arises as a comorbidity in patients with MPNs—than BMT recipients from CalrWT/WT mice, with pulmonary arterial remodeling accompanied by an accumulation of donor-derived macrophages in response to chronic hypoxia. In conclusion, our murine model with the frameshifted murine Calr presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.

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Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms

Abstract: Key Points• In patients with MPNs, repression of MIRlet-7 and mutations in the polycomb genes EZH2 and ASXL1 correlate with HMGA2 overexpression.• Hmga2 overexpression collaborates with JAK2V617F to promote lethal MPN in mice, highlighting the crucial role of Hmga2.

Cited by 17 publications

References 64 publications

LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis

LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis

Crucial role of hematopoietic <i>JAK2</i> V617F in the development of aortic aneurysms

Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice

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