Gene Mutation Characteristics and Prognostic Significance in Acute Myeloid Leukemia Patients From Northeast China
This article is part of Special Issue:
Yiyang Shen,
Shuang Fu,
Xuan Liu,
Jianing Liu,
Yu Fu,
Yue Zhao,
Xinxin Wang,
Xujian Jiang,
Jihong Zhang,
Yiyang Shen
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorShuang Fu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXuan Liu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorJianing Liu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorYu Fu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorYue Zhao
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXinxin Wang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXujian Jiang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorCorresponding Author
Jihong Zhang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorYiyang Shen,
Shuang Fu,
Xuan Liu,
Jianing Liu,
Yu Fu,
Yue Zhao,
Xinxin Wang,
Xujian Jiang,
Jihong Zhang,
Yiyang Shen
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorShuang Fu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXuan Liu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorJianing Liu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorYu Fu
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorYue Zhao
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXinxin Wang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorXujian Jiang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorCorresponding Author
Jihong Zhang
Hematology Laboratory , Shengjing Hospital of China Medical University , Shenyang , China , cmu.edu.cn
Search for more papers by this authorFirst published: 20 February 2025
Academic Editor: Aziz ur Rehman Aziz
Abstract
A great part of studies on the correlation between gene mutations and prognosis in acute myeloid leukemia (AML) patients are based on Western populations. To profile the genomic landscape of AML patients in Northeast China, we retrospectively analyzed the clinical data of 377 newly diagnosed AML patients in Shengjing Hospital of China Medical University from 2016 to 2022 and compared them with data from other populations with different genetic backgrounds. The mutation status of NPM1, FLT3-ITD, FLT3-TKD, CEBPA (CCAT enhancer binding protein alpha), ASXL1, TET2, KIT, DNMT3A (DNA methyltransferase 3A), IDH1, IDH2, EZH2 (enhancer of zeste 2), RUNX1, TP53, NRAS, and GATA2 was acquired by next-generation sequencing (NGS) technology; meanwhile, the clinical data of the patients were collected. The Cox regression model was used to analyze factors affecting patient survival and the impact of CEBPA and DNMT3A mutation on prognosis, and the results were different from those in other populations. Seventy-seven of 377 patients (20.4%) were detected with CEBPA mutations, which was higher than the 2%–6% in the Caucasian population. In the CEBPAdm patients who did not receive bone marrow transplantation, the prognosis of male patients (n = 18) was significantly better than that of female patients (n = 21) (p = 0.0242). Sixty-three of 377 patients (16.7%) carried the DNMT3A mutation, which was lower than the mutation frequency of 20.9% in the German–Austrian population, and the prognosis of these patients was significantly poorer (p = 0.0052). In addition, the prognostic evaluation value of the DNMT3A mutation in AML patients was not affected regardless of the presence of the NPM1 and FLT3-ITD comutation (p > 0.05), nor the mutation site of DNMT3A. In conclusion, for the Northeastern Chinese population, the prognosis of male patients with CEBPAdm was more favorable than that of female patients, and the DNMT3A mutation serves as an independent predictor of poor prognosis in AML. These results highlighted the central role of genetic background in precision medicine strategies and further emphasized the importance of the clinical characteristics of AML gene mutations in the Chinese population.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The clinical data of patients used to support the findings of this study are available from the corresponding author upon request.
Supporting Information
| Filename | Description |
|---|---|
| humu7730186-sup-0001-f1.docxWord 2007 document , 60.6 KB | Supporting Information Additional supporting information can be found online in the Supporting Information section. Figure S1: OS of the patients younger than 30 years old versus the patients between 30 and 39 years old. For Table 1, descriptive analysis was conducted on clinical data such as age, WBC count, and PLT count for all patients, male patients, and female patients. Additionally, t-tests were performed to compare these indicators between male and female patients. Chi-square tests were used to compare chromosomal changes, FAB classifications, and mutation status between male and female patients. For Figures 1, 3, 4, 5, 6, 7, 8, and 9 and Table 4, univariate Cox proportional hazards regression analysis was conducted. Table 5 presents the results of multivariate Cox proportional hazards regression analysis. Chi-square tests were utilized for Tables 2 and 3. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 DiNardo C. D., Erba H. P., Freeman S. D., and Wei A. H., Acute myeloid leukaemia, The Lancet. (2023) 401, no. 10393, 2073–2086, https://doi.org/10.1016/S0140-6736(23)00108-3.
- 2 Zheng R., Zhang S., Zeng H., Wang S., Sun K., Chen R., Li L., Wei W., and He J., Cancer incidence and mortality in China, 2016, Journal of the National Cancer Center. (2022) 2, no. 1, 1–9, https://doi.org/10.1016/j.jncc.2022.02.002, 39035212.
- 3 Yang F., Anekpuritanang T., and Press R. D., Clinical utility of next-generation sequencing in acute myeloid leukemia, Molecular Diagnosis & Therapy. (2020) 24, no. 1, 1–13, https://doi.org/10.1007/s40291-019-00443-9.
- 4 Döhner H., Wei A. H., Appelbaum F. R., Craddock C., DiNardo C. D., Dombret H., Ebert B. L., Fenaux P., Godley L. A., Hasserjian R. P., Larson R. A., Levine R. L., Miyazaki Y., Niederwieser D., Ossenkoppele G., Röllig C., Sierra J., Stein E. M., Tallman M. S., Tien H.-F., Wang J., Wierzbowska A., and Löwenberg B., Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN, Blood. (2022) 140, no. 12, 1345–1377, https://doi.org/10.1182/blood.2022016867, 35797463.
- 5 Chen J., Yang H., Teo A. S. M., Amer L. B., Sherbaf F. G., Tan C. Q., Alvarez J. J. S., Lu B., Lim J. Q., Takano A., Nahar R., Lee Y. Y., Phua C. Z. J., Chua K. P., Suteja L., Chen P. J., Chang M. M., Koh T. P. T., Ong B.-H., Anantham D., Hsu A. A. L., Gogna A., Too C. W., Aung Z. W., Lee Y. F., Wang L., Lim T. K. H., Wilm A., Choi P. S., Ng P. Y., Toh C. K., Lim W.-T., Ma S., Lim B., Liu J., Tam W. L., Skanderup A. J., Yeong J. P. S., Tan E.-H., Creasy C. L., Tan D. S. W., Hillmer A. M., and Zhai W., Genomic landscape of lung adenocarcinoma in East Asians, Nature Genetics. (2020) 52, no. 2, 177–186, https://doi.org/10.1038/s41588-019-0569-6, 32015526.
- 6 Li J., Xu C., Lee H. J., Ren S., Zi X., Zhang Z., Wang H., Yu Y., Yang C., Gao X., Hou J., Wang L., Yang B., Yang Q., Ye H., Zhou T., Lu X., Wang Y., Qu M., Yang Q., Zhang W., Shah N. M., Pehrsson E. C., Wang S., Wang Z., Jiang J., Zhu Y., Chen R., Chen H., Zhu F., Lian B., Li X., Zhang Y., Wang C., Wang Y., Xiao G., Jiang J., Yang Y., Liang C., Hou J., Han C., Chen M., Jiang N., Zhang D., Wu S., Yang J., Wang T., Chen Y., Cai J., Yang W., Xu J., Wang S., Gao X., Wang T., and Sun Y., A genomic and epigenomic atlas of prostate cancer in Asian populations, Nature. (2020) 580, no. 7801, 93–99, https://doi.org/10.1038/s41586-020-2135-x, 32238934.
- 7 Liu T., Rao J., Hu W., Cui B., Cai J., Liu Y., Sun H., Chen X., Tang Y., Chen J., Wang X., Wang H., Qian W., Mao B., Guo S., Wang R., Liu Y., and Shen S., Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification, Nature Communications. (2022) 13, no. 1, https://doi.org/10.1038/s41467-022-29336-y, 35347147.
- 8 Tyner J. W., Tognon C. E., Bottomly D., Wilmot B., Kurtz S. E., Savage S. L., Long N., Schultz A. R., Traer E., Abel M., Agarwal A., Blucher A., Borate U., Bryant J., Burke R., Carlos A., Carpenter R., Carroll J., Chang B. H., Coblentz C., d’Almeida A., Cook R., Danilov A., Dao K. H. T., Degnin M., Devine D., Dibb J., Edwards V. D. K., Eide C. A., English I., Glover J., Henson R., Ho H., Jemal A., Johnson K., Johnson R., Junio B., Kaempf A., Leonard J., Lin C., Liu S. Q., Lo P., Loriaux M. M., Luty S., Macey T., MacManiman J., Martinez J., Mori M., Nelson D., Nichols C., Peters J., Ramsdill J., Rofelty A., Schuff R., Searles R., Segerdell E., Smith R. L., Spurgeon S. E., Sweeney T., Thapa A., Visser C., Wagner J., Watanabe-Smith K., Werth K., Wolf J., White L., Yates A., Zhang H., Cogle C. R., Collins R. H., Connolly D. C., Deininger M. W., Drusbosky L., Hourigan C. S., Jordan C. T., Kropf P., Lin T. L., Martinez M. E., Medeiros B. C., Pallapati R. R., Pollyea D. A., Swords R. T., Watts J. M., Weir S. J., Wiest D. L., Winters R. M., McWeeney S. K., and Druker B. J., Functional genomic landscape of acute myeloid leukaemia, Nature. (2018) 562, no. 7728, 526–531, https://doi.org/10.1038/s41586-018-0623-z, 2-s2.0-85055455410, 30333627.
- 9 Duan R., Du W., and Guo W., EZH2: a novel target for cancer treatment, Journal of Hematology & Oncology. (2020) 13, no. 1, https://doi.org/10.1186/s13045-020-00937-8, 32723346.
- 10 Perrone S., Ottone T., Zhdanovskaya N., and Molica M., How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?, Cancer Drug Resistance. (2023) 6, no. 2, 223–238, https://doi.org/10.20517/cdr.2022.130, 37457126.
- 11 Bhansali R. S., Pratz K. W., and Lai C., Recent advances in targeted therapies in acute myeloid leukemia, Journal of Hematology & Oncology. (2023) 16, no. 1, https://doi.org/10.1186/s13045-023-01424-6, 36966300.
- 12 Li Y. and Zhu B., Acute myeloid leukemia with DNMT3A mutations, Leukemia & Lymphoma. (2014) 55, no. 9, 2002–2012, https://doi.org/10.3109/10428194.2013.869802, 2-s2.0-84900388467.
- 13 Su L., Shi Y.-Y., Liu Z.-Y., and Gao S.-J., Acute myeloid leukemia with CEBPA mutations: current progress and future directions, Frontiers in Oncology. (2022) 12, 806137, https://doi.org/10.3389/fonc.2022.806137, 35178345.
- 14 Wang S., Zhang Y.-X., Huang T., Sui J.-N., Lu J., Chen X.-J., Wang K.-K., Xi X.-D., Li J.-M., Huang J.-Y., and Chen B., Mutation profile and associated clinical features in Chinese patients with cytogenetically normal acute myeloid leukemia, International Journal of Laboratory Hematology. (2018) 40, no. 4, 408–418, https://doi.org/10.1111/ijlh.12802, 2-s2.0-85044263126, 29573577.
- 15 Bullinger L., CEBPA mutations in AML: site matters, Blood. (2022) 139, no. 1, 6–7, https://doi.org/10.1182/blood.2021013557.
- 16 Fasan A., Haferlach C., Alpermann T., Jeromin S., Grossmann V., Eder C., Weissmann S., Dicker F., Kohlmann A., Schindela S., Kern W., Haferlach T., and Schnittger S., The role of different genetic subtypes of CEBPA mutated AML, Leukemia. (2014) 28, no. 4, 794–803, https://doi.org/10.1038/leu.2013.273, 2-s2.0-84898051374, 24056881.
- 17 Taube F., Georgi J. A., Kramer M., Stasik S., Middeke J. M., Röllig C., Krug U., Krämer A., Scholl S., Hochhaus A., Brümmendorf T. H., Naumann R., Petzold A., Mulet-Lazaro R., Valk P. J. M., Steffen B., Einsele H., Schaich M., Burchert A., Neubauer A., Schäfer-Eckart K., Schliemann C., Krause S. W., Hänel M., Noppeney R., Kaiser U., Baldus C. D., Kaufmann M., Herold S., Stölzel F., Sockel K., von Bonin M., Müller-Tidow C., Platzbecker U., Berdel W. E., Serve H., Ehninger G., Bornhäuser M., Schetelig J., Thiede C., and for the Study Alliance Leukemia (SAL), CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome, Blood. (2022) 139, no. 1, 87–103, https://doi.org/10.1182/blood.2020009680, 34320176.
- 18 Tarlock K., Lamble A. J., Wang Y.-C., Gerbing R. B., Ries R. E., Loken M. R., Brodersen L. E., Pardo L., Leonti A., Smith J. L., Hylkema T. A., Woods W. G., Cooper T. M., Kolb E. A., Gamis A. S., Aplenc R., Alonzo T. A., and Meshinchi S., CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children’s Oncology Group, Blood. (2021) 138, no. 13, 1137–1147, https://doi.org/10.1182/blood.2020009652, 33951732.
- 19 Yang L., Rau R., and Goodell M. A., DNMT3A in haematological malignancies, Nature Reviews Cancer. (2015) 15, no. 3, 152–165, https://doi.org/10.1038/nrc3895, 2-s2.0-84923580247, 25693834.
- 20 Ley T. J., Ding L., Walter M. J., McLellan M. D., Lamprecht T., Larson D. E., Kandoth C., Payton J. E., Baty J., Welch J., Harris C. C., Lichti C. F., Townsend R. R., Fulton R. S., Dooling D. J., Koboldt D. C., Schmidt H., Zhang Q., Osborne J. R., Lin L., O′Laughlin M., McMichael J. F., Delehaunty K. D., McGrath S. D., Fulton L. A., Magrini V. J., Vickery T. L., Hundal J., Cook L. L., Conyers J. J., Swift G. W., Reed J. P., Alldredge P. A., Wylie T., Walker J., Kalicki J., Watson M. A., Heath S., Shannon W. D., Varghese N., Nagarajan R., Westervelt P., Tomasson M. H., Link D. C., Graubert T. A., DiPersio J. F., Mardis E. R., and Wilson R. K., DNMT3A mutations in acute myeloid leukemia, The New England Journal of Medicine. (2010) 363, no. 25, 2424–2433, https://doi.org/10.1056/NEJMoa1005143, 2-s2.0-78649906060, 21067377.
- 21 Park D. J., Kwon A., Cho B.-S., Kim H.-J., Hwang K.-A., Kim M., and Kim Y., Characteristics of DNMT3A mutations in acute myeloid leukemia, Blood Research. (2020) 55, no. 1, 17–26, https://doi.org/10.5045/br.2020.55.1.17, 32269971.
- 22 Jawad M., Afkhami M., Ding Y., Zhang X., Li P., Young K., Xu M. L., Cui W., Zhao Y., Halene S., Al-Kali A., Viswanatha D., Chen D., He R., and Zheng G., DNMT3A R882 mutations confer unique clinicopathologic features in MDS including a high risk of AML transformation, Frontiers in Oncology. (2022) 12, 849376, https://doi.org/10.3389/fonc.2022.849376, 35296003.
- 23 Gaidzik V. I., Schlenk R. F., Paschka P., Stölzle A., Späth D., Kuendgen A., von Lilienfeld-Toal M., Brugger W., Derigs H. G., Kremers S., Greil R., Raghavachar A., Ringhoffer M., Salih H. R., Wattad M., Kirchen H. G., Runde V., Heil G., Petzer A. L., Girschikofsky M., Heuser M., Kayser S., Goehring G., Teleanu M.-V., Schlegelberger B., Ganser A., Krauter J., Bullinger L., Döhner H., and Döhner K., Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG), Blood. (2013) 121, no. 23, 4769–4777, https://doi.org/10.1182/blood-2012-10-461624, 2-s2.0-84881051116.
- 24 Sun Y., Shen H., Xu T., Yang Z., Qiu H., Sun A., Chen S., Wu D., and Xu Y., Persistent DNMT3A mutation burden in DNMT3A mutated adult cytogenetically normal acute myeloid leukemia patients in long-term remission, Leukemia Research. (2016) 49, 102–107, https://doi.org/10.1016/j.leukres.2016.09.001, 2-s2.0-84986536861, 27626217.
- 25 Gaidzik V. I., Weber D., Paschka P., Kaumanns A., Krieger S., Corbacioglu A., Krönke J., Kapp-Schwoerer S., Krämer D., Horst H. A., Schmidt-Wolf I., Held G., Kündgen A., Ringhoffer M., Götze K., Kindler T., Fiedler W., Wattad M., Schlenk R. F., Bullinger L., Teleanu V., Schlegelberger B., Thol F., Heuser M., Ganser A., Döhner H., Döhner K., and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG), DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia, Leukemia. (2018) 32, no. 1, 30–37, https://doi.org/10.1038/leu.2017.200, 2-s2.0-85048507718.
- 26 Döhner H., Estey E., Grimwade D., Amadori S., Appelbaum F. R., Büchner T., Dombret H., Ebert B. L., Fenaux P., Larson R. A., Levine R. L., Lo-Coco F., Naoe T., Niederwieser D., Ossenkoppele G. J., Sanz M., Sierra J., Tallman M. S., Tien H.-F., Wei A. H., Löwenberg B., and Bloomfield C. D., Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel, Blood. (2017) 129, no. 4, 424–447, https://doi.org/10.1182/blood-2016-08-733196, 2-s2.0-85014879329, 27895058.
- 27 Sasaki K., Ravandi F., Kadia T. M., DiNardo C. D., Short N. J., Borthakur G., Jabbour E., and Kantarjian H. M., De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017, Cancer. (2021) 127, no. 12, 2049–2061, https://doi.org/10.1002/cncr.33458, 33818756.
- 28 Srivastava V. M., Nair S. C., Sappani M., Manipadam M.-T., Kulkarni U. P., Devasia A. J., Fouzia N. A., Korula A., Lakshmi K. M., Abraham A., and Srivastava A., Cytogenetic profile of 1791 adult acute myeloid leukemia in India, Molecular Cytogenetics. (2023) 16, no. 1, https://doi.org/10.1186/s13039-023-00653-1, 37716945.
- 29 Capra M., Vilella L., Pereira W. V., Coser V. M., Fernandes M. S., Schilling M. A., Almeida D., Gross M., Leite M., Hellwig T., Natchigal G., Zelmanowicz A., Paskulin G., Neumann J., and Silla L., Estimated number of cases, regional distribution and survival of patients diagnosed with acute myeloid leukemia between 1996 and 2000 in Rio Grande do Sul, Brazil, Leukemia & Lymphoma. (2007) 48, no. 12, 2381–2386, https://doi.org/10.1080/10428190701713622, 2-s2.0-37149030594, 18067014.
- 30 Wilhelmson A. S. and Porse B. T., CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance, British Journal of Haematology. (2020) 190, no. 4, 495–507, https://doi.org/10.1111/bjh.16534, 32086816.
- 31 Cheng W.-Y., Li J.-F., Zhu Y.-M., Lin X.-J., Wen L.-J., Zhang F., Zhang Y.-L., Zhao M., Fang H., Wang S.-Y., Lin X.-J., Qiao N., Yin W., Zhang J.-N., Dai Y.-T., Jiang L., Sun X.-J., Xu Y., Zhang T.-T., Chen S.-N., Zhu H.-H., Chen Z., Jin J., Wu D.-P., Shen Y., and Chen S.-J., Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia, Proceedings of the National Academy of Sciences of the United States of America. (2022) 119, no. 49, e2211429119, https://doi.org/10.1073/pnas.2211429119, 36442087.
- 32 Wakita S., Sakaguchi M., Oh I., Kako S., Toya T., Najima Y., Doki N., Kanda J., Kuroda J., Mori S., Satake A., Usuki K., Ueki T., Uoshima N., Kobayashi Y., Kawata E., Tajika K., Nagao Y., Shono K., Shibusawa M., Tadokoro J., Kayamori K., Hagihara M., Uchiyama H., Uchida N., Kubota Y., Kimura S., Nagoshi H., Ichinohe T., Kurosawa S., Motomura S., Hashimoto A., Muto H., Sato E., Ogata M., Mitsuhashi K., Ando J., Marumo A., Omori I., Fujiwara Y., Terada K., Yui S., Arai K., Kitano T., Miyata M., Kurosawa A., Mizoguchi A., Komatsu N., Fukuda T., Ohashi K., Kanda Y., Inokuchi K., and Yamaguchi H., Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia, Blood Advances. (2022) 6, no. 1, 238–247, https://doi.org/10.1182/bloodadvances.2021004292, 34448807.
- 33 Papaemmanuil E., Gerstung M., Bullinger L., Gaidzik V. I., Paschka P., Roberts N. D., Potter N. E., Heuser M., Thol F., Bolli N., Gundem G., Van Loo P., Martincorena I., Ganly P., Mudie L., McLaren S., O’Meara S., Raine K., Jones D. R., Teague J. W., Butler A. P., Greaves M. F., Ganser A., Döhner K., Schlenk R. F., Döhner H., and Campbell P. J., Genomic classification and prognosis in acute myeloid leukemia, The New England Journal of Medicine. (2016) 374, no. 23, 2209–2221, https://doi.org/10.1056/NEJMoa1516192, 2-s2.0-84973879698, 27276561.
- 34 Wakita S., Marumo A., Morita K., Kako S., Toya T., Najima Y., Doki N., Kanda J., Kuroda J., Mori S., Satake A., Usuki K., Ueki T., Uoshima N., Kobayashi Y., Kawata E., Nakayama K., Nagao Y., Shono K., Shibusawa M., Tadokoro J., Hagihara M., Uchiyama H., Uchida N., Kubota Y., Kimura S., Nagoshi H., Ichinohe T., Kurosawa S., Motomura S., Hashimoto A., Muto H., Sato E., Ogata M., Mitsuhashi K., Ando J., Tashiro H., Sakaguchi M., Yui S., Arai K., Kitano T., Miyata M., Arai H., Kanda M., Itabashi K., Fukuda T., Kanda Y., and Yamaguchi H., Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia, Cancer Science. (2023) 114, no. 4, 1297–1308, https://doi.org/10.1111/cas.15720, 36610002.
- 35 Renneville A., Boissel N., Nibourel O., Berthon C., Helevaut N., Gardin C., Cayuela J. M., Hayette S., Reman O., Contentin N., Bordessoule D., Pautas C., Botton S., Revel T., Terre C., Fenaux P., Thomas X., Castaigne S., Dombret H., and Preudhomme C., Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association, Leukemia. (2012) 26, no. 6, 1247–1254, https://doi.org/10.1038/leu.2011.382, 2-s2.0-84862007674, 22289988.
- 36 Thol F., Damm F., Lüdeking A., Winschel C., Wagner K., Morgan M., Yun H., Göhring G., Schlegelberger B., Hoelzer D., Lübbert M., Kanz L., Fiedler W., Kirchner H., Heil G., Krauter J., Ganser A., and Heuser M., Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia, Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. (2011) 29, no. 21, 2889–2896, https://doi.org/10.1200/JCO.2011.35.4894, 2-s2.0-79960735923.
- 37 Bullinger L., Döhner K., and Döhner H., Genomics of acute myeloid leukemia diagnosis and pathways, Journal of Clinical Oncology. (2017) 35, no. 9, 934–946, https://doi.org/10.1200/JCO.2016.71.2208, 2-s2.0-85016263999.
- 38 Oñate G., Bataller A., Garrido A., Hoyos M., Arnan M., Vives S., Coll R., Tormo M., Sampol A., Escoda L., Salamero O., Garcia A., Bargay J., Aljarilla A., Nomdedeu J. F., Esteve J., Sierra J., and Pratcorona M., Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1, Blood Advances. (2022) 6, no. 3, 882–890, https://doi.org/10.1182/bloodadvances.2020004136, 34516636.
- 39 Gaidzik V. I., Teleanu V., Papaemmanuil E., Weber D., Paschka P., Hahn J., Wallrabenstein T., Kolbinger B., Köhne C. H., Horst H. A., Brossart P., Held G., Kündgen A., Ringhoffer M., Götze K., Rummel M., Gerstung M., Campbell P., Kraus J. M., Kestler H. A., Thol F., Heuser M., Schlegelberger B., Ganser A., Bullinger L., Schlenk R. F., Döhner K., Döhner H., and for the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG), RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features, Leukemia. (2016) 30, no. 11, 2160–2168, https://doi.org/10.1038/leu.2016.126, 2-s2.0-84973659562.
- 40 Greif P. A., Konstandin N. P., Metzeler K. H., Herold T., Pasalic Z., Ksienzyk B., Dufour A., Schneider F., Schneider S., Kakadia P. M., Braess J., Sauerland M. C., Berdel W. E., Buchner T., Woermann B. J., Hiddemann W., Spiekermann K., and Bohlander S. K., RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes, Haematologica. (2012) 97, no. 12, 1909–1915, https://doi.org/10.3324/haematol.2012.064667, 2-s2.0-84870437993, 22689681.
- 41 Kim Y.-K., Kim H.-N., Lee S. R., Ahn J.-S., Yang D.-H., Lee J.-J., Lee I.-K., Shin M.-G., and Kim H.-J., Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia, The Korean Journal of Hematology. (2010) 45, no. 1, 36–45, https://doi.org/10.5045/kjh.2010.45.1.36, 21120161.
- 42 Wang L., Xu W., Meng H., Qian W., Mai W., Tong H., Mao L., Tong Y., Qian J., Lou Y., Chen Z., Wang Y., and Jin J., FLT3 and NPM1 mutations in Chinese patients with acute myeloid leukemia and normal cytogenetics, Journal of Zhejiang University. Science. B. (2010) 11, no. 10, 762–770, https://doi.org/10.1631/jzus.B1000052, 2-s2.0-77958002838, 20872983.
- 43 Lachowiez C. A., Long N., Saultz J., Gandhi A., Newell L. F., Hayes-Lattin B., Maziarz R. T., Leonard J., Bottomly D., McWeeney S., Dunlap J., Press R., Meyers G., Swords R., Cook R. J., Tyner J. W., Druker B. J., and Traer E., Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia, Blood Advances. (2023) 7, no. 9, 1899–1909, https://doi.org/10.1182/bloodadvances.2022009010.
- 44 Paschka P., Du J., Schlenk R. F., Gaidzik V. I., Bullinger L., Corbacioglu A., Späth D., Kayser S., Schlegelberger B., Krauter J., Ganser A., Köhne C.-H., Held G., von Lilienfeld-Toal M., Kirchen H., Rummel M., Götze K., Horst H.-A., Ringhoffer M., Lübbert M., Wattad M., Salih H. R., Kündgen A., Döhner H., and Döhner K., Secondary genetic lesions in acute myeloid leukemia with inv (16) or t (16;16): a study of the German-Austrian AML Study Group (AMLSG), Blood. (2013) 121, no. 1, 170–177, https://doi.org/10.1182/blood-2012-05-431486, 2-s2.0-84872056078.
- 45 Care R. S., Valk P. J. M., Goodeve A. C., Abu-Duhier F. M., Geertsma-Kleinekoort W. M. C., Wilson G. A., Gari M. A., Peake I. R., Löwenberg B., and Reilly J. T., Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias, British Journal of Haematology. (2003) 121, no. 5, 775–777, https://doi.org/10.1046/j.1365-2141.2003.04362.x, 2-s2.0-0038170400, 12780793.
- 46 Paschka P., Marcucci G., Ruppert A. S., Mrózek K., Chen H., Kittles R. A., Vukosavljevic T., Perrotti D., Vardiman J. W., Carroll A. J., Kolitz J. E., Larson R. A., Bloomfield C. D., and Cancer and Leukemia Group B, Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv (16) and t(8;21): a Cancer and Leukemia Group B study, Journal of Clinical Oncology. (2006) 24, no. 24, 3904–3911, https://doi.org/10.1200/JCO.2006.06.9500, 2-s2.0-33748467435, 16921041.
- 47 Zhang F., Shen Z., Xie J., Zhang J., Wu Q., Jiang R., Zhao X., Yang X., and Chen S., CEBPA bZIP in-frame mutations in acute myeloid leukemia: prognostic and therapeutic implications, Blood Cancer Journal. (2024) 14, no. 1, https://doi.org/10.1038/s41408-024-01042-6, 38594276.
- 48 Falini B. and Dillon R., Criteria for diagnosis and molecular monitoring ofNPM1-Mutated AML, Blood Cancer Discovery. (2024) 5, no. 1, 8–20, https://doi.org/10.1158/2643-3230.BCD-23-0144.
- 49 Gamlen H. A., Romer-Seibert J. S., Lawler M. E., Versace A. M., Goetz M. L., Feng Y., Guryanova O. A., Palmisiano N., and Meyer S. E., miR-196b-TLR7/8 signaling axis regulates innate immune signaling and myeloid maturation in DNMT3A-mutant AML, Clinical Cancer Research. (2022) 28, no. 20, 4574–4586, https://doi.org/10.1158/1078-0432.CCR-22-1598, 35943291.
