CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Greenblatt Sarah M.; Man Na; Hamard Pierre-Jacques; Asai Takashi; Karl Daniel; Martinez Concepcion; Bilbao Daniel; Stathais Vasileios; McGrew-Jermacowicz Anna; Duffort Stephanie; Tadi Madhavi; Blumenthal Ezra; Newman Samantha; Vu Ly; Xu Ye; Liu Fan; Schurer Stephan C.; McCabe Michael T.; Kruger Ryan G.; Xu Mingjiang; Yang Feng-Chun; Tenen Daniel; Watts Justin; Vega Francisco; Nimer Stephen D.

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CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

机译：CARM1对于骨髓性白血病，对于正常血缺乏症来说是必不可少的

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Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML.

机译：染色质修饰酶，特别是蛋白质精氨酸甲基转移酶（PRMT），已成为癌症的重要靶点。在这里，我们研究了CARM1在正常和恶性造血中的作用。使用条件敲除小鼠，我们发现CARM1的缺失对正常造血几乎没有影响。引人注目的是，Carm1基因的敲除消除了由致癌转录因子驱动的急性髓系白血病（AML）的发生和维持。我们发现CARM1基因敲除会损害细胞周期进程，促进髓系分化，并最终诱导细胞凋亡。最后，我们利用选择性小分子CARM1抑制剂在体外和体内验证CARM1抑制白血病细胞的效果。总之，这项研究表明，针对CARM1可能是AML的一种有效治疗策略。

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《Cancer Cell》 |2018年第6期|共22页
作者
Greenblatt Sarah M.; Man Na; Hamard Pierre-Jacques; Asai Takashi; Karl Daniel; Martinez Concepcion; Bilbao Daniel; Stathais Vasileios; McGrew-Jermacowicz Anna; Duffort Stephanie; Tadi Madhavi; Blumenthal Ezra; Newman Samantha; Vu Ly; Xu Ye; Liu Fan; Schurer Stephan C.; McCabe Michael T.; Kruger Ryan G.; Xu Mingjiang; Yang Feng-Chun; Tenen Daniel; Watts Justin; Vega Francisco; Nimer Stephen D.;
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Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

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Cellular Pharmacol Miami FL 33136 USA;

Univ Miami Dept Mol &

Cellular Pharmacol Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

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Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

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GlaxoSmithKline Oncol R&

D Canc Epigenet Discovery Performance Unit 1250 S Collegeville Rd;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Harvard Med Sch Harvard Stem Cell Inst Boston MA 02115 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA;

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1. Zinc finger and BTB domain-containing protein 46 is essential for survival and proliferation of acute myeloid leukemia cell line but dispensable for normal hematopoiesis [J] . Yuan-Yuan Liu, Xing-Qin Huang, Guang-Ling Zheng, 中华医学杂志（英文版） . 2020,第014期
2. Essential role of DOT IL in maintaining normal adul hematopoiesis [J] . 无细胞研究：英文版 . 2011,第009期
3. Essential role of DOT1L in maintaining normal adult hematopoiesis [J] . Anh T Nguyen, Jin He, Olena Taranova, 细胞研究（英文版） . 2011,第009期
4. Epigenetic Silencing of Eyes Absent 4 Gene by Acute Myeloid Leukemia 1-Eight-twenty-one Oncoprotein Contributes to Leukemogenesis in t(8;21) Acute Myeloid Leukemia [J] . Sai Huang, Meng-Meng Jiang, Guo-Feng Chen, 中华医学杂志（英文版） . 2016,第011期
5. Dual role for atypical chemokine receptor 1 in myeloid cell hematopoiesis and distribution [J] . Marc Permanyer, Berislav Bošnjak, Reinhold Förster 细胞与分子免疫学：英文版 . 2018,第004期
6. CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis (vol 33, pg 1111, 2018) [J] . Greenblatt Sarah M., Man Na, Hamard Pierre-Jacques, Cancer Cell . 2019,第1期

机译：CARM1对于骨髓性白血病，对于正常血管缺陷（Vol 33，PG 1111,2018）来说是必不可少的
7. CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis [J] . Greenblatt Sarah M., Man Na, Hamard Pierre-Jacques, Cancer Cell . 2018,第6期

机译：CARM1对于骨髓性白血病至关重要，但对于正常的血液缺血，可分配
8. CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis (vol 33, pg 1111, 2018) [J] . Greenblatt Sarah M., Man Na, Hamard Pierre-Jacques, Cancer Cell . 2018,第5期

机译：CARM1对于骨髓性白血病，对于正常血管缺陷（Vol 33，PG 1111,2018）来说是必不可少的
9. Proteogenomic profiling of acute myeloid leukemia reveals novel insights into leukemogenesis [C] . Sandow JJ, Ghisi M, Garnham A, ASMS Conference on Mass Spectrometry and Allied Topics . 2016

机译：急性髓性白血病的突畴样素揭示了对白血病的新洞察力
10. Loss of Egr1 plays a role in murine leukemogenesis and may play a role in the development of acute myeloid leukemia and therapy-related acute myeloid leukemia. [D] . Joslin, John M. 2006

机译：Egr1的丢失在小鼠白血病的发生中起作用，并且可能在急性髓细胞性白血病和与治疗有关的急性髓细胞性白血病的发展中起作用。
11. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis [O] . Sarah M. Greenblatt, Na Man, Pierre-Jacques Hamard, -1

机译：CARM1对于髓样白血病的形成是必不可少的但对于正常的造血作用是必不可少的
12. CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis [O] . Sarah M. Greenblatt, Na Man, Pierre-Jacques Hamard, 2019

机译：CARM1对于骨髓性白血病至关重要，但对于正常的血液缺血，可分配
13. Thymic Regulation of Hematopoiesis: Myeloid Differentiation in the Stem Cell Defective W/Wv Mouse. [R] . Sharkis, S. J., Ahmed, A., Sensenbrenner, L. L., 1978

机译：血细胞生成的胸腺调节：干细胞缺陷W / Wv小鼠的骨髓分化。

CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

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