Research progress of mixed lineage leukemia in malignant hematologic disease
-
摘要:
混合谱系白血病(MLL)基因是果蝇组蛋白赖氨酸N-甲基转移酶2(KMT2)基因的哺乳动物同源物, 编码一种特异性针对组蛋白H3第4位赖氨酸(H3K4)的甲基转移酶。MLL蛋白家族共有6个成员(MLL1、MLL2、MLL3、MLL4、SETD1A和SETD1B), 是哺乳动物发育过程中重要的表观遗传调控因子，在造血系统中对造血干细胞的增殖和分化发挥重要作用。MLL家族基因突变与恶性血液病的发生密切相关，且常提示预后不良。深入了解MLL的异常改变及其作用机制有助于相关肿瘤的诊断、靶向药物的研发和预后的判断，现将MLL基因在恶性血液病中的研究进展综述如下。
Abstract:The mixed lineage leukemia (MLL) gene, a mammalian homolog of the drosophila histone lysine N-methyltransferase 2(KMT2) gene, encodes a methyltransferase that specifically targets lysine 4 of histone H3 (H3K4). There are six members of MLL protein family (MLL1, MLL2, MLL3, MLL4, SETD1A, SETD1B), which are important epigenetic regulators in mammalian development and play an important role in proliferation and differentiation of hematopoietic stem cells. MLL mutations are closely related to the occurrence of hematologic malignancies and often indicate poor prognosis. Deep understanding the abnormal changes of MLL and its mechanism of action are helpful for the diagnosis of related tumors, the development of targeted drugs and the prognosis. This article focused on the MLL gene and its research progress in hematologic malignancies.
-
Keywords:
- mixed lineage leukemia /
- methylation /
- hematologic malignancy /
- targeted therapy
-
-
[1] ZIEMIN-VAN DER POEL S, MCCABE N R, GILL H J, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias[J]. Proc Natl Acad Sci U S A, 1991, 88(23): 10735-10739. doi: 10.1073/pnas.88.23.10735
[2] SUN C, ZHANG X D, RUZYCKI P A, et al. Essential functions of MLL1 and MLL2 in retinal development and cone cell maintenance[J]. Front Cell Dev Biol, 2022, 10: 829536. doi: 10.3389/fcell.2022.829536
[3] CRUMP N T, MILNE T A. Why are so many MLL lysine methyltransferases required for normal mammalian development[J]. Cell Mol Life Sci, 2019, 76(15): 2885-2898. doi: 10.1007/s00018-019-03143-z
[4] SHA L, AYOUB A, CHO U S, et al. Insights on the regulation of the MLL/SET1 family histone methyltransferases[J]. Biochim Biophys Acta Gene Regul Mech, 2020, 1863(7): 194561. doi: 10.1016/j.bbagrm.2020.194561
[5] SUGEEDHA J, GAUTAM J, TYAGI S. SET1/MLL family of proteins: functions beyond histone methylation[J]. Epigenetics, 2021, 16(5): 469-487. doi: 10.1080/15592294.2020.1809873
[6] YANG L, JIN M L, JEONG K W. Histone H3K4 methyltransferases as targets for drug-resistant cancers[J]. Biology, 2021, 10(7): 581. doi: 10.3390/biology10070581
[7] JAIN K, FRASER C S, MARUNDE M R, et al. Characterization of the plant homeodomain (PHD) reader family for their histone tail interactions[J]. Epigenetics Chromatin, 2020, 13(1): 3. doi: 10.1186/s13072-020-0328-z
[8] LI X, SONG Y C. Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins[J]. J Hematol Oncol, 2021, 14(1): 56. doi: 10.1186/s13045-021-01057-7
[9] YANG Y D, JOSHI M, TAKAHASHI Y H, et al. A non-canonical monovalent zinc finger stabilizes the integration of Cfp1 into the H3K4 methyltransferase complex COMPASS[J]. Nucleic Acids Res, 2020, 48(1): 421-431.
[10] POREBA E, LESNIEWICZ K, DURZYNSKA J. Histone-lysine N-methyltransferase 2 (KMT2) complexes - a new perspective[J]. Mutat Res Rev Mutat Res, 2022, 790: 108443. doi: 10.1016/j.mrrev.2022.108443
[11] LI Y J, HAN J M, ZHANG Y B, et al. Structural basis for activity regulation of MLL family methyltransferases[J]. Nature, 2016, 530(7591): 447-452. doi: 10.1038/nature16952
[12] ARYAL S, ZHANG Y, WREN S, et al. Molecular regulators of HOXA9 in acute myeloid leukemia[J]. FEBS J, 2023, 290(2): 321-339. doi: 10.1111/febs.16268
[13] MIYAMOTO R, KANAI A, OKUDA H, et al. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways[J]. Elife, 2021, 10: e64148. doi: 10.7554/eLife.64148
[14] WEN J Q, ZHOU M, SHEN Y L, et al. Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements[J]. BMC Cancer, 2022, 22(1): 859. doi: 10.1186/s12885-022-09804-w
[15] NGUYEN D, KANTARJIAN H M, SHORT N J, et al. Early mortality in acute myeloid leukemia with KMT2A rearrangement is associated with high risk of bleeding and disseminated intravascular coagulation[J]. Cancer, 2023, 129(12): 1856-1865. doi: 10.1002/cncr.34728
[16] MEYER C, BURMEISTER T, GRÖGER D, et al. The MLL recombinome of acute leukemias in 2017[J]. Leukemia, 2018, 32(2): 273-284. doi: 10.1038/leu.2017.213
[17] CHEN Y, CRAMER P. Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization[J]. J Biol Chem, 2019, 294(27): 10663-10673. doi: 10.1074/jbc.RA119.008577
[18] YUAN Y N, DU L, TAN R L, et al. Design, synthesis, and biological evaluations of DOT1L peptide mimetics targeting the protein-protein interactions between DOT1L and MLL-AF9/MLL-ENL[J]. J Med Chem, 2022, 65(11): 7770-7785. doi: 10.1021/acs.jmedchem.2c00083
[19] LEI H, ZHANG S Q, FAN S, et al. Recent progress of small molecule menin-MLL interaction inhibitors as therapeutic agents for acute leukemia[J]. J Med Chem, 2021, 64(21): 15519-15533. doi: 10.1021/acs.jmedchem.1c00872
[20] TAKAHASHI S, YOKOYAMA A. The molecular functions of common and atypical MLL fusion protein complexes[J]. Biochim Biophys Acta BBA Gene Regul Mech, 2020, 1863(7): 194548. doi: 10.1016/j.bbagrm.2020.194548
[21] YOKOYAMA A. Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system[J]. Cancer Sci, 2021, 112(10): 3935-3944. doi: 10.1111/cas.15054
[22] SMITH M J, OTTONI E, ISHIYAMA N, et al. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia[J]. Nat Commun, 2017, 8(1): 1099. doi: 10.1038/s41467-017-01326-5
[23] CHEN B R, DESHPANDE A, BARBOSA K, et al. A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML[J]. Blood, 2021, 137(24): 3403-3415. doi: 10.1182/blood.2020009023
[24] FAGAN R J, DINGWALL A K. COMPASS Ascending: emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer[J]. Cancer Lett, 2019, 458: 56-65. doi: 10.1016/j.canlet.2019.05.024
[25] POREBA E, LESNIEWICZ K, DURZYNSKA J. Aberrant activity of histone-lysine N-methyltransferase 2 (KMT2) complexes in oncogenesis[J]. Int J Mol Sci, 2020, 21(24): 9340. doi: 10.3390/ijms21249340
[26] ORTEGA-MOLINA A, BOSS I W, CANELA A, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development[J]. Nat Med, 2015, 21(10): 1199-1208. doi: 10.1038/nm.3943
[27] ZHANG J Y, DOMINGUEZ-SOLA D, HUSSEIN S, et al. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis[J]. Nat Med, 2015, 21(10): 1190-1198. doi: 10.1038/nm.3940
[28] SANTOS M A, FARYABI R B, ERGEN A V, et al. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier[J]. Nature, 2014, 514(7520): 107-111. doi: 10.1038/nature13483
[29] HUANG L, LIU D, WANG N, et al. Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia[J]. Cell Res, 2018, 28(2): 172-186. doi: 10.1038/cr.2017.146
[30] CHEN Y F, ANASTASSIADIS K, KRANZ A, et al. MLL2, not MLL1, plays a major role in sustaining MLL-rearranged acute myeloid leukemia[J]. Cancer Cell, 2017, 31(6): 755-770. e6. doi: 10.1016/j.ccell.2017.05.002
[31] CHEN C, LIU Y, RAPPAPORT A R, et al. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia[J]. Cancer Cell, 2014, 25(5): 652-665. doi: 10.1016/j.ccr.2014.03.016
[32] HOSHII T, CIFANI P, FENG Z H, et al. A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response[J]. Cell, 2018, 172(5): 1007-1021. e17. doi: 10.1016/j.cell.2018.01.032
[33] BRANFORD S, KIM D D H, APPERLEY J F, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia[J]. Leukemia, 2019, 33(8): 1835-1850. doi: 10.1038/s41375-019-0512-y
[34] YI Y, GE S L. Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias[J]. J Hematol Oncol, 2022, 15(1): 35. doi: 10.1186/s13045-022-01251-1
[35] BARGHOUT S H, MACHADO R A C, BARSYTE-LOVEJOY D. Chemical biology and pharmacology of histone lysine methylation inhibitors[J]. Biochim Biophys Acta BBA Gene Regul Mech, 2022, 1865(6): 194840. doi: 10.1016/j.bbagrm.2022.194840
[36] DINARDO K W, LEBLANC T W, CHEN H. Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting[J]. J Hematol Oncol, 2023, 16(1): 17. doi: 10.1186/s13045-023-01411-x
[37] AUBREY B J, CUTLER J A, BOURGEOIS W, et al. IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia[J]. Nat Cancer, 2022, 3(5): 595-613. doi: 10.1038/s43018-022-00366-1
[38] LIU L L, GUO X, WANG Y, et al. Loss of Wdr5 attenuates MLL-rearranged leukemogenesis by suppressing myc targets[J]. Biochim Biophys Acta Mol Basis Dis, 2023, 1869(2): 166600. doi: 10.1016/j.bbadis.2022.166600
[39] CHEN W L, CHEN X, LI D D, et al. Discovery of DDO-2213 as a potent and orally bioavailable inhibitor of the WDR5-mixed lineage leukemia 1 protein-protein interaction for the treatment of MLL fusion leukemia[J]. J Med Chem, 2021, 64(12): 8221-8245. doi: 10.1021/acs.jmedchem.1c00091
[40] ZHAO L J, HUANG N Z, MENCIUS J, et al. DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates[J]. iScience, 2022, 25(9): 104948. doi: 10.1016/j.isci.2022.104948
[41] SHAH K K, WHITAKER R H, BUSBY T, et al. Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth[J]. Exp Cell Res, 2019, 382(2): 111485. doi: 10.1016/j.yexcr.2019.06.030
[42] KALMODE H P, PODSIADLY I, KABRA A, et al. Small-molecule inhibitors of the MLL1 CXXC domain, an epigenetic reader of DNA methylation[J]. ACS Med Chem Lett, 2022, 13(8): 1363-1369. doi: 10.1021/acsmedchemlett.2c00198
[43] CANTILENA S, GASPAROLI L, PAL D, et al. Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias[J]. Clin Transl Med, 2022, 12(6): e933.
[44] UCKUN F M, QAZI S. Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance[J]. Cancer Drug Resist, 2022, 5(10): 902-916. doi: 10.20517/cdr.2022.78
-
期刊类型引用(14)
1. 汤骏姣. 对接受内镜下止血治疗的消化道出血患者进行时间护理的效果分析. 当代医药论丛. 2020(02): 257-259 . 
百度学术
2. 裴艳苓. 时间护理对消化道出血患者止血的效果及健康知识指标的影响评价. 中国医药指南. 2020(08): 288-289 . 百度学术
3. 刘洁羽. 优质护理模式对上消化道出血患者康复质量及满意度的影响. 辽宁医学杂志. 2020(02): 81-83 . 百度学术
4. 王英姿. 个体化系统护理在上消化道出血急救中的应用效果. 黑龙江中医药. 2020(01): 268-269 . 百度学术
5. 张艳. 针对性预防护理在消化道出血患者中的应用效果. 中国当代医药. 2019(02): 245-247 . 百度学术
6. 刘坤. 时间护理对消化道出血患者止血的效果及健康知识的价值体会. 世界最新医学信息文摘. 2019(17): 285-286 . 百度学术
7. 李闻新, 张余, 部实, 张雪柏, 闫宇青, 张福林, 卢占斌. 3种质子泵抑制药预防颈脊髓损伤患者应激性溃疡的最小成本分析. 中国药师. 2019(05): 870-872 . 百度学术
8. 缪君芳. 时间护理联合常规护理在脑梗塞患者中的护理效果观察. 智慧健康. 2019(32): 135-136 . 百度学术
9. 汤天娟. 时间护理对消化道出血患者止血的效果及健康知识指标的影响评价. 中西医结合心血管病电子杂志. 2019(32): 113-114 . 百度学术
10. 李韦韦, 楚建杰, 胡冬梅, 赵先, 王婧雯. 某院国产和进口奥曲肽治疗上消化道出血的成本-效果分析. 中国医院药学杂志. 2018(04): 440-442+449 . 百度学术
11. 高媛媛, 李新萍, 连凯敏. 消化道出血患者的临床观察及护理要点探究. 中国农村卫生. 2018(17): 55+57 . 百度学术
12. 邵菊香. 时间护理对肝硬化合并消化道出血患者止血的效果及健康知识的影响效果分析. 中国农村卫生. 2018(24): 57-58 . 百度学术
13. 刘晓霞. 68例上消化道出血患者的临床观察及护理. 世界最新医学信息文摘. 2017(55): 183+191 . 百度学术
14. 颜爱丽. 时间护理对消化道出血患者止血的效果及健康知识的影响研究. 现代医学与健康研究电子杂志. 2017(09): 111 . 百度学术
其他类型引用(1)
计量
- 文章访问数: 186
- HTML全文浏览量: 98
- PDF下载量: 29
- 被引次数: 15
下载:
苏公网安备 32100302010246号
