A global study for acute myeloid leukemia with RARG rearrangement

Author:

Zhu Hong-Hu1ORCID,Qin Ya-Zhen2ORCID,Zhang Zhang-Lin3,Liu Yong-Jing4ORCID,Wen Li-Jun5,You M. James6,Zhang Cheng7,Such Esperanza8ORCID,Luo Hong9,Yuan Hong-Jian10,Zhou Hong-Sheng11,Liu Hong-Xing12ORCID,Xu Reng13,Li Ji14,Li Jian-Hu15,Hao Jian-Ping16,Jin Jie15,Yu Liang17,Zhang Jing-Ying18,Liu Li-Ping19,Zhang Le-Ping20,Huang Rui-Bin21,Shen Shu-Hong22,Gao Su-Jun23,Wang Wei24,Yan Xiao-Jing25ORCID,Zhang Xin-You26,Du Xin27,Chu Xiao-Xia28,Yu Yan-Fang29,Wang Yi30,Mi Ying-Chang31,Lu Ying32,Cai Zhen33ORCID,Su Zhan34,Taussig David Christopher35,MacMahon Suzanne35,Ball Edward D.36,Wang Huan-You36,Welch John S.37ORCID,Yin C. Cameron6ORCID,Borthakur Gautam38,Sanz Miguel A.8ORCID,Kantarjian Hagop M.38,Huang Jin-Yan4ORCID,Hu Jiong39,Chen Su-Ning5ORCID

Affiliation:

1. 1Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

2. 2Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China

3. 3Department of Transfusion, Institute of Transfusion, Jiangxi Key Laboratory of Transfusion, The First Affiliated Hospital of Nanchang University, Nanchang, China

4. 4Biomedical Big Data Center, The First Affiliated Hospital, Zhejiang University, Hangzhou, China

5. 5National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

6. 6Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX

7. 7Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, China

8. 8Hematology Department, Hospital La Fe, Valencia, Spain

9. 9Department of Hematology, The First Hospital of Qiqihar, Heilongjiang, Qiqihar, China

10. 10Department of Hematology, The Second People's Hospital of Taizhou, Taizhou, China

11. 11Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China

12. 12Molecular Medicine Center, Beijing Lu Daopei lnstitute of Hematology, Beijing, China

13. 13Shanghai Righton Biotechnology Co. Ltd, Shanghai, China

14. 14Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

15. 15Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, China

16. 16Department of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China

17. 17Department of Hematology, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huaian, China

18. 18Department of Hematology-Oncology, The Children Hospital of Zhejiang University School of Medicine, Zhejiang Childhood Leukemia Diagnosis and Treatment Technology Research Center, National Medical Research Center for Child Health, Hangzhou, China

19. 19Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China

20. 20Department of Pediatrics, Peking University People's Hospital, Beijing, China

21. 21Department of Hematology, The First Affiliated hospital of Nanchang University, Nanchang, China

22. 22Department of Hematology/Oncology, National Children's Medical Center, Key Laboratory of Pediatric Hematology and Oncology of China Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

23. 23Department of Hematology, the First Hospital of Jilin University, Changchun, Jilin, China

24. 24Department of Hematology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China

25. 25Department of Hematology, First Hospital of China Medical University, Shenyang, China

26. 26Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China

27. 27Department of Hematology, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China

28. 28Department of Hematology, Qindao University Medical College, Affiliated Yantai Yuhuangding Hospital, Yantai, China

29. 29Department of Hematology, Peking University Shougang Hospital, Beijing, China

30. 30Department of Hematology, Provincial People Hospital, Xian, Shaanxi, China

31. 31Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China

32. 32Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China

33. 33Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

34. 34Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China

35. 35Centre for Molecular Pathology, The Royal Marsden, Institute of Cancer Research, Sutton, United Kingdom

36. 36Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego, La Jolla, CA

37. 37Department of Internal Medicine, Washington University, St. Louis, MO

38. 38Department of Leukemia, MD Anderson Cancer Center, Houston, TX

39. 39Department of Hematology, Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, and Collaborative Innovation Center of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Abstract

Abstract Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).

Publisher

American Society of Hematology

Subject

Hematology

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