The Characteristics and Outcomes of Adult Acute Myeloid Leukemia Patients With KMT2A-Partial Tandem Duplication
Dai-Hong Xie
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorWen-Min Chen
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorYue Hao
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorXu Wang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorLing-Di Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorJin-Ying Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorZhao-Yu Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorHao Jiang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorQian Jiang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorXiao-Jun Huang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorCorresponding Author
Ya-Zhen Qin
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Correspondence:
Ya-Zhen Qin ([email protected])
Search for more papers by this authorDai-Hong Xie
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorWen-Min Chen
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorYue Hao
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorXu Wang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorLing-Di Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorJin-Ying Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorZhao-Yu Li
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorHao Jiang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorQian Jiang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorXiao-Jun Huang
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Search for more papers by this authorCorresponding Author
Ya-Zhen Qin
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
Correspondence:
Ya-Zhen Qin ([email protected])
Search for more papers by this authorFunding: This work was supported by the National Nature Science Foundation of China (81870125).
ABSTRACT
Introduction
KMT2A-Partial Tandem Duplication (KMT2A-PTD) is a recurrent gene mutation present in acute myeloid leukemia (AML) and its prognostic significance needs to be clarified.
Methods
Three hundred and eighty-seven consecutive adult newly diagnosed AML patients with non-favorable cytogenetic risk were tested for KMT2A-PTD by real-time quantitative PCR. All patients were screened for AML-related gene fusions and mutations.
Results
Thirty-two (8.3%) patients were identified as KMT2A-PTD (+). KMT2A-PTD significantly co-occurred with FLT3-ITD, RUNX1, and DNMT3A mutation and tended to be related to normal karyotype (p < 0.0001, p = 0.0001, 0.019, and 0.062). Furthermore, none of the KMT2A-PTD (+) patients had NPM1 mutation, CEBPA bZIP in-frame mutation (p = 0.0005 and 0.0009), and none of them had KMT2A-rearrangement and other gene fusions (p = 0.16). As a result, all KMT2A-PTD (+) patients were categorized into ELN2022-intermediate or adverse groups (p < 0.0001). KMT2A-PTD was not related to patients' age, sex, white blood cell (WBC) counts, hemoglobin (Hb) level, platelet (PLT) counts, percentage of bone marrow blast cells, and FAB subtypes (all p > 0.05). KMT2A-PTD had no effect on complete remission achievement after 1 and 2 courses of induction therapy, relapse-free survival, and overall survival in both the entire cohort and within the following five subgroups: FLT3-ITD (+), RUNX1 mutation, DNMT3A mutation, ELN2022-intermediate, and ELN2022-adverse categories, respectively (all p > 0.05). Moreover, KMT2A-PTD (+) patients also could not be stratified by them (all p > 0.05).
Conclusion
KMT2A-PTD harbored its distinct genetic characteristics and had no prognostic impacts in AML.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijlh14532-sup-0001-Figures.pdfPDF document, 407.1 KB |
Figure S1. The effects of FLT3-ITD, RUNX1 mutation and DNMT3A mutation on CR rates after first and second cycles of induction therapy. Numbers in the figure represented the p values. Figure S2. The CR rates after first and second cycles of induction therapy between ELN2022 genetic risk classification. Numbers in the figure represented the p values. Figure S3. The RFS and OS curves of FLT3-ITD, RUNX1 mutation, DNMT3A mutation and ELN2022 genetic risk classifications. Figure S4. The impact of FLT3-ITD (a, e), RUNX1 mutation (b, f), DNMT3A mutation (c, g) and ELN2022 genetic risk classification (d, h) on patients’ outcomes in KMT2A-PTD (+) patient. |
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
- 1L. F. Newell and R. J. Cook, “Advances in Acute Myeloid Leukemia,” BMJ 375 (2021): n2026, https://doi.org/10.1136/bmj.n2026.
- 2A. Khwaja, M. Bjorkholm, R. E. Gale, et al., “Acute Myeloid Leukaemia,” Nature Reviews Disease Primers 2 (2016): 1–22, https://doi.org/10.1038/nrdp.2016.10.
- 3K. H. Metzeler, T. Herold, M. Rothenberg-Thurley, et al., “Spectrum and Prognostic Relevance of Driver Gene Mutations in Acute Myeloid Leukemia,” Blood 128 (2016): 686–698, https://doi.org/10.1182/blood-2016-01-693879.
- 4S. Kayser and M. J. Levis, “The Clinical Impact of the Molecular Landscape of Acute Myeloid Leukemia,” Haematologica 108 (2023): 308–320, https://doi.org/10.3324/haematol.2022.280801.
- 5P. Ernst, J. Wang, and S. J. Korsmeyer, “The Role of MLL in Hematopoiesis and Leukemia,” Current Opinion in Hematology 9 (2002): 282–287, https://doi.org/10.1097/00062752-200207000-00004.
- 6S. A. Schichman, M. A. Caligiuri, Y. Gu, et al., “ALL-1 Partial Duplication in Acute Leukemia,” Proceedings of the National Academy of Sciences of the United States of America 91 (1994): 6236–6239, https://doi.org/10.1073/pnas.91.13.6236.
- 7J. Basecke, J. T. Whelan, F. Griesinger, and F. E. Bertrand, “The MLL Partial Tandem Duplication in Acute Myeloid Leukaemia,” British Journal of Haematology 135 (2006): 438–449, https://doi.org/10.1111/j.1365-2141.2006.06301.x.
- 8M. E. Martin, T. A. Milne, S. Bloyer, et al., “Dimerization of MLL Fusion Proteins Immortalizes Hematopoietic Cells,” Cancer Cell 4 (2003): 197–207, https://doi.org/10.1016/s1535-6108(03)00214-9.
- 9S. P. Whitman, S. Liu, T. Vukosavljevic, et al., “The MLL Partial Tandem Duplication: Evidence for Recessive Gain-Of-Function in Acute Myeloid Leukemia Identifies a Novel Patient Subgroup for Molecular-Targeted Therapy,” Blood 106 (2005): 345–352, https://doi.org/10.1182/blood-2005-01-0204.
- 10A. M. Dorrance, S. Liu, A. Chong, et al., “The Mll Partial Tandem Duplication: Differential, Tissue-Specific Activity in the Presence or Absence of the Wild-Type Allele,” Blood 112 (2008): 2508–2511, https://doi.org/10.1182/blood-2008-01-134338.
- 11S. Schnittger, U. Kinkelin, C. Schoch, et al., “Screening for MLL Tandem Duplication in 387 Unselected Patients With AML Identify a Prognostically Unfavorable Subset of AML,” Leukemia 14 (2000): 796–804, https://doi.org/10.1038/sj.leu.2401773.
- 12K. Döhner, K. Tobis, R. Ulrich, et al., “Prognostic Significance of Partial Tandem Duplications of the MLL Gene in Adult Patients 16 to 60 Years Old With Acute Myeloid Leukemia and Normal Cytogenetics: A Study of the Acute Myeloid Leukemia Study Group Ulm,” Journal of Clinical Oncology 20 (2002): 3254–3261, https://doi.org/10.1200/JCO.2002.09.088.
- 13C. Steudel, M. Wermke, M. Schaich, et al., “Comparative Analysis of MLL Partial Tandem Duplication and FLT3 Internal Tandem Duplication Mutations in 956 Adult Patients With Acute Myeloid Leukemia,” Genes, Chromosomes & Cancer 37 (2003): 237–251, https://doi.org/10.1002/gcc.10219.
- 14L. Muñoz, J. F. Nomdedéu, N. Villamor, et al., “Acute Myeloid Leukemia With MLL Rearrangements: Clinicobiological Features, Prognostic Impact and Value of Flow Cytometry in the Detection of Residual Leukemic Cells,” Leukemia 17 (2003): 76–82, https://doi.org/10.1038/sj.leu.2402708.
- 15M. Weisser, W. Kern, C. Schoch, W. Hiddemann, T. Haferlach, and S. Schnittger, “Risk Assessment by Monitoring Expression Levels of Partial Tandem Duplications in the MLL Gene in Acute Myeloid Leukemia During Therapy,” Haematologica 90, no. 7 (2005): 881–889.
- 16L. Shih, D. Liang, J. Fu, et al., “Characterization of Fusion Partner Genes in 114 Patients With de Novo Acute Myeloid Leukemia and MLL Rearrangement,” Leukemia 20 (2006): 218–223, https://doi.org/10.1038/sj.leu.2404024.
- 17S. P. Whitman, A. S. Ruppert, G. Marcucci, et al., “Long-Term Disease-Free Survivors With Cytogenetically Normal Acute Myeloid Leukemia and MLL Partial Tandem Duplication: A Cancer and Leukemia Group B Study,” Blood 109 (2007): 5164–5167, https://doi.org/10.1182/blood-2007-01-069831.
- 18H. Döhner, A. H. Wei, F. R. Appelbaum, et al., “Diagnosis and Management of AML in Adults: 2022 Recommendations From an International Expert Panel on Behalf of the ELN,” Blood 140 (2022): 1345–1377, https://doi.org/10.1182/blood.2022016867.
- 19R. Alaggio, C. Amador, I. Anagnostopoulos, et al., “The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms,” Leukemia 36 (2022): 1720–1748, https://doi.org/10.1038/s41375-022-01620-2.
- 20O. K. Weinberg, A. Porwit, A. Orazi, et al., “The International Consensus Classification of Acute Myeloid Leukemia,” Virchows Archiv 482 (2023): 27–37, https://doi.org/10.1007/s00428-022-03430-4.
- 21G.-R. Ruan, J.-L. Li, Y.-Z. Qin, et al., “Nucleophosmin Mutations in Chinese Adults With Acute Myelogenous Leukemia,” Annals of Hematology 88 (2009): 159–166, https://doi.org/10.1007/s00277-008-0591-8.
- 22N. Xu, W.-M. Chen, L.-D. Li, et al., “High WT1 Expression Predicted Induction Chemotherapy Failure in Acute Myeloid Leukemia Patients With Non-Favorable Cytogenetic Risk,” Clinical and Experimental Medicine 23 (2023): 2629–2638, https://doi.org/10.1007/s10238-023-00995-5.
- 23J. Wang, R. Lu, Y. Wu, et al., “Detection of Measurable Residual Disease May Better Predict Outcomes Than Mutations Based on Next-Generation Sequencing in Acute Myeloid Leukaemia With Biallelic Mutations of CEBPA,” British Journal of Haematology 190 (2020): 533–544, https://doi.org/10.1111/bjh.16535.
- 24 Leukemia & Lymphoma Group, Chinese Society of Hematology, Chinese Medical Association, “Chinese Guidelines for the Diagnosis and Treatment of Adult Acute Myeloid Leukemia (not APL),” Zhonghua Xue Ye Xue Za Zhi 42 (2021): 617–623, https://doi.org/10.3760/cma.j.issn.0253-2727.2021.08.001.
- 25Y. Wang, Y.-J. Chang, J. Chen, et al., “Consensus on the Monitoring, Treatment, and Prevention of Leukaemia Relapse After Allogeneic Haematopoietic Stem Cell Transplantation in China: 2024 Update,” Cancer Letters 605 (2024): 217264, https://doi.org/10.1016/j.canlet.2024.217264.
- 26S. Yu, T. Lin, D. Nie, et al., “Dynamic Assessment of Measurable Residual Disease in Favorable-Risk Acute Myeloid Leukemia in First Remission, Treatment, and Outcomes,” Blood Cancer Journal 11 (2021): 1–9, https://doi.org/10.1038/s41408-021-00591-4.
- 27C. Thiede, “MLL-PTD as a Marker for Minimal Residual Disease Studies: Quantification Counts,” Haematologica 90 (2005): 865.
- 28J. Kong, M.-G. Gao, Y.-Z. Qin, et al., “Monitoring of Post-Transplant MLL-PTD as Minimal Residual Disease Can Predict Relapse After Allogeneic HSCT in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome,” BMC Cancer 22 (2022): 11, https://doi.org/10.1186/s12885-021-09051-5.
- 29A. C. Winters and K. M. Bernt, “MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches,” Frontiers in Pediatrics 5 (2017): 4, https://doi.org/10.3389/fped.2017.00004.
- 30H. Döhner, E. Estey, D. Grimwade, et al., “Diagnosis and Management of AML in Adults: 2017 ELN Recommendations From an International Expert Panel,” Blood 129 (2017): 424–447, https://doi.org/10.1182/blood-2016-08-733196.
- 31A.-K. Eisfeld, J. Kohlschmidt, K. Mrózek, et al., “Adult Acute Myeloid Leukemia With Trisomy 11 as the Sole Abnormality is Characterized by the Presence of Five Distinct Gene Mutations: MLL-PTD, DNMT3A, U2AF1, FLT3-ITD and IDH2,” Leukemia 30 (2016): 2254–2258, https://doi.org/10.1038/leu.2016.196.
- 32G. Rege-Cambrin, E. Giugliano, L. Michaux, et al., “Trisomy 11 in Myeloid Malignancies Is Associated With Internal Tandem Duplication of Both MLL and FLT3 Genes,” Haematologica 90 (2005): 262–264.
- 33R. Jamal, T. Taketani, T. Taki, et al., “Coduplication of the MLL and FLT3 Genes in Patients With Acute Myeloid Leukemia,” Genes, Chromosomes and Cancer 31 (2001): 187–190, https://doi.org/10.1002/gcc.1132.
- 34A. M. Dorrance, S. Liu, W. Yuan, et al., “Mll Partial Tandem Duplication Induces Aberrant Hox Expression in Vivo via Specific Epigenetic Alterations,” Journal of Clinical Investigation 116 (2006): 2707–2716, https://doi.org/10.1172/JCI25546.
- 35Y. Zhang, X. Yan, G. Sashida, et al., “Stress Hematopoiesis Reveals Abnormal Control of Self-Renewal, Lineage Bias, and Myeloid Differentiation in Mll Partial Tandem Duplication (Mll-PTD) Hematopoietic Stem/Progenitor Cells,” Blood 120 (2012): 1118–1129, https://doi.org/10.1182/blood-2012-02-412379.
- 36H.-W. Kao, D.-C. Liang, M.-C. Kuo, et al., “High Frequency of Additional Gene Mutations in Acute Myeloid Leukemia With MLL Partial Tandem Duplication: DNMT3A Mutation Is Associated With Poor Prognosis,” Oncotarget 6 (2015): 33217–33225, https://doi.org/10.18632/oncotarget.5202.
- 37Q.-Y. Sun, L.-W. Ding, K.-T. Tan, et al., “Ordering of Mutations in Acute Myeloid Leukemia With Partial Tandem Duplication of MLL (MLL-PTD),” Leukemia 31 (2017): 1–10, https://doi.org/10.1038/leu.2016.160.
- 38J. Kong, X.-S. Zhao, Y.-Z. Qin, et al., “The Initial Level of MLL -Partial Tandem Duplication Affects the Clinical Outcomes in Patients With Acute Myeloid Leukemia,” Leukemia & Lymphoma 59 (2018): 967–972, https://doi.org/10.1080/10428194.2017.1352091.
- 39M. A. Caligiuri, S. A. Schichman, M. P. Strout, et al., “Molecular Rearrangement of the ALL-1 Gene in Acute Myeloid Leukemia Without Cytogenetic Evidence of 11q23 Chromosomal Translocations,” Cancer Research 54 (1994): 370–373.
- 40A. S. Mims, A. Mishra, S. Orwick, et al., “A Novel Regimen for Relapsed/Refractory Adult Acute Myeloid Leukemia Using a KMT2A Partial Tandem Duplication Targeted Therapy: Results of Phase 1 Study NCI 8485,” Haematologica 103 (2018): 982–987, https://doi.org/10.3324/haematol.2017.186890.
Online Version of Record before inclusion in an issue
