变异型急性早幼粒细胞白血病表型特征和治疗效果评估相关进展

doi:10.3969/j.issn.1673-8640.2025.06.016

摘要/Abstract

摘要：

急性早幼粒细胞白血病（APL）是急性髓系白血病（AML）的独特亚型，有超过98%的患者属于经典型APL，表达PML::RARα融合基因，对全反式维甲酸（ATRA）和三氧化二砷（ATO）诱导分化敏感，临床疗效良好。与经典型APL比较，变异型APL表现出不同的临床和形态学特征，对ATRA的反应也不同。文章对变异型APL的临床特征、发病率、实验室检测和对ATRA、ATO、化疗的敏感性，以及患者预后进行总结和分析，并绘制变异型APL的3D基因融合图谱，探讨其在APL发生中的作用和对ATRA的作用机制。

关键词: 变异型急性早幼粒细胞白血病, 全反式维甲酸, 临床特征, 转归

Abstract:

Acute promyelocytic leukemia（APL） is a unique subtype of acute myeloid leukemia（AML），more than 98% of patients belong to typical APL，expressing PML::RARα，sensitive to all-trans retinoic acid（ATRA） and arsenic trioxide（ATO） induced differentiation，and its clinical effect is good. Variant APL exhibits different clinical and morphologic characteristics and responds differently to ATRA compared with classic APL. This review summarizes and analyzes the clinical characteristics，incidence rate，laboratory determinations，sensitivities to ATRA，ATO and chemotherapy，as well as the prognosis of patients with variant APL. It also draws the 3D gene fusion profile of variant APL to investigate its role in the occurrence of APL and its mechanism of ATRA.

Key words: Variant acute promyelocytic leukemia, All-trans retinoic acid, Clinical characteristic, Out-come

中图分类号:

R446.1

马镜云, 王萌萌, 熊博钰, 戴卓文, 潘月月, 王琼. 变异型急性早幼粒细胞白血病表型特征和治疗效果评估相关进展[J]. 检验医学, 2025, 40(6): 606-614.

MA Jingyun, WANG Mengmeng, XIONG Boyu, DAI Zhuowen, PAN Yueyue, WANG Qiong. Research progress in phenotypic characteristics and treatment efficacy evaluation of acute promyelocytic leukemia variants[J]. Laboratory Medicine, 2025, 40(6): 606-614.

图/表 2

参考文献 34

[1]	SANZ M A, BARRAGÁN E. History of acute promyelocytic leukemia[J]. Clin Hematol Int, 2021, 3(4):142-152.
[2]	ALOTAIBI A S, ABDULRAZZAQ M, PATEL K P, et al. Acute promyelocytic leukemia(APL)with an IRF2BP2-RARα fusion transcript:an aggressive APL variant[J]. Leuk Lymphoma, 2020, 61(12):3018-3020.
[3]	IYER S G, ELIAS L, STANCHINA M, et al. The treatment of acute promyelocytic leukemia in 2023:paradigm,advances,and future directions[J]. Front Oncol, 2023, 12:1062524.
[4]	FENG X, ZHENG Y, XU J. Morphology and clinical characteristics of a case of FIP1L1-RARα fusion-associated variant acute promyelocytic leukemia[J]. Leuk Lymphoma, 2023, 64(2):499-502.
[5]	GUARNERA L, OTTONE T, FABIANI E, et al. Atypical rearrangements in APL-like acute myeloid leukemias:molecular characterization and prognosis[J]. Front Oncol, 2022, 12:871590.
[6]	ABOU-GHALI M, LALLEMAND-BREITENBACH V. PML nuclear bodies:the cancer connection and beyond[J]. Nucleus, 2024, 15(1):2321265.
[7]	TROMBETTI S, CESARO E, CATAPANO R, et al. Oxidative stress and ROS-mediated signaling in leukemia:novel promising perspectives to eradicate chemoresistant cells in myeloid leukemia[J]. Int J Mol Sci, 2021, 22(5):2470.
[8]	PASTOR T P, PEIXOTO B C, VIOLA J P B. The transcriptional co-factor IRF2BP2:a new player in tumor development and microenvironment[J]. Front Cell Dev Biol, 2021, 9:655307.
[9]	ZHANG X, SUN J, YU W, et al. Current views on the genetic landscape and management of variant acute promyelocytic leukemia[J]. Biomark Res, 2021, 9(1):33. DOI PMID
[10]	KWON H, YUN M, KWON T H, et al. Fibronectin type Ⅲ domain containing 3B as a potential prognostic and therapeutic biomarker for glioblastoma[J]. Biomedicines, 2023, 11(12):3168.
[11]	CHEN Y, LI M, WU H, et al. Arsenic trioxide induces proteasome dependent TBLR1-RARα degradation to improve leukemia eradication through cell differentiation enhancement[J]. J Cancer, 2022, 13(7):2301-2311.
[12]	LIU G, LONG J, CHEN Y, et al. Acute promyelocytic leukemia with FIP1L1::RARα fusion gene:the clinical utility of transcriptome sequencing and bioinformatic analyses[J]. Front Oncol, 2023, 12:1049473.
[13]	SHIMOSATO Y, YAMAMOTO K, JIA Y, et al. NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation[J]. Leukemia, 2025, 39(1):75-86.
[14]	NATHANY S, TRIPATHI R, MEHTA A. Gene of the month:GTF2I[J]. J Clin Pathol, 2021, 74(1):1-4.
[15]	XU J, LI H, WANG Z, et al. Venetoclax overcomes resistance to all-trans retinoic acid in a variant acute promyelocytic leukemia with TNRC18::RARα fusion[J]. Mol Carcinog, 2024, 63(4):553-557.
[16]	WANG Z, WEN L, ZHANG L, et al. Identification of a novel TNRC18-RARΑ fusion in acute promyelocytic leukemia lacking t(15;17)(q24;q12)/PML-RARΑ[J]. Mol Carcinog, 2021, 60(2):101-105.
[17]	SÁNCHEZ-VILLANUEVA J A, N'GUYEN L, POPLINEAU M, et al. Predictive modelling of acute promyelocytic leukaemia resistance to retinoic acid therapy[J]. Brief Bioinform, 2024, 26(1):bbaf002.
[18]	DUAN X, LIU B, YANG M. Refractory acute promyelocytic leukemia with PLZF/RARa rearrangement:a case report and literature review[J]. Anticancer Drugs, 2023, 34(5):690-694.
[19]	LI H, XIANG X, DING H, et al. Differentiation therapy using low-dose venetoclax in a variant acute promyelocytic leukaemia carrying ZBTB16-RARα[J]. Br J Haematol, 2022, 199(5):768-771.
[20]	CASTELIJN D A R, SIJM G, VENNIKER-PUNT B, et al. An acute promyelocytic leukemia resistant to all-trans retinoic acid:a case report of the ZBTB16::RARa variant and review of the literature[J]. Case Rep Oncol, 2023, 16(1):1443-1450.
[21]	ZHU H H, YANG M C, WANG F, et al. Identification of a novel NUP98-RARα fusion transcript as the 14th variant of acute promyelocytic leukemia[J]. Am J Hematol, 2020, 95(7):E184-E186.
[22]	LIU M, ZHAO X, PAN W, et al. A novel HNRNPC-RARα fusion in acute promyelocytic leukaemia lacking PML-RARα rearrangement,sensitive to venetoclax-based therapy[J]. Br J Haematol, 2021, 195(2):e123-e128.
[23]	LIU K, YOU B, DUNCAN J, et al. FISH signal pattern for an APL variant translocation with a PRKAR1A-RARα fusion[J]. J Assoc Genet Technol, 2022, 48(4):176-177.
[24]	CICCONI L, TESTI A M, MONTESINOS P, et al. Characteristics and outcome of acute myeloid leukemia with uncommon retinoic acid receptor-alpha(RARα)fusion variants[J]. Blood Cancer J, 2021, 11(10):167.
[25]	TAO T, CEN J, XU C, et al. Identification of concurrent STAT3::RARα and RARα::STAT5b fusions in a variant APL case[J]. Mol Carcinog, 2024, 63(4):558-562.
[26]	KUMAR S, TCHOUNWOU P B. Arsenic trioxide reduces the expression of E2F1,cyclin E,and phosphorylation of PI3K signaling molecules in acute leukemia cells[J]. Environ Toxicol, 2021, 36(9):1785-1792.
[27]	PATTERSON J, CLARKE K, MOKRETAR K, et al. Treatment of a STAT5b::RARα positive case of APL in a patient not eligible for intensive chemotherapy[J]. Ir J Med Sci, 2024, 193(6):2875-2881.
[28]	WANG L, YAN X, HE J. Does acute promyelocytic leukemia patient with the STAT5B/RARa fusion gene respond well to decitabine?:a case report and literature review[J]. Medicine(Baltimore), 2020, 99(43):e22923.
[29]	TSAI H K, SABBAGH M F, MONTESION M, et al. Acute promyelocytic leukemia with torque teno mini virus::RARα fusion:an approach to screening and diagnosis[J]. Mod Pathol, 2024, 37(7):100509.
[30]	LOU J, ZHANG Y, TAO J, et al. Infection-related pathway activation and vulnerability to arsenic trioxide in acute promyelocytic leukemia with TTMV::RARα[J]. Leukemia, 2025, 39(2):490-494.
[31]	CHICANO M, CARBONELL D, SUÁREZ-GONZÁLEZ J, et al. Next generation cytogenetics in myeloid hematological neoplasms:detection of CNVs and translocations[J]. Cancers(Basel), 2021, 13(12):3001.
[32]	UHRIG S, ELLERMANN J, WALTHER T, et al. Accurate and efficient detection of gene fusions from RNA sequencing data[J]. Genome Res, 2021, 31(3):448-460. DOI PMID
[33]	BORUTINSKAITĖ V, ŽUČENKA A, VITKEVIČIENĖ A, et al. Genetic and epigenetic signatures in acute promyelocytic leukemia treatment and molecular remission[J]. Front Genet, 2022, 13:821676.
[34]	SCALZULLI E, COSTA A, CARMOSINO I, et al. Different prognosis according to treatment in patients with acute promyelocytic leukemia:how the outcome changed over time[J]. Ann Hematol, 2024, 103(12):5377-5386.

融合染色体	融合基因	变异型APL发生情况	对ATRA的反应	对ATO的反应	参考文献
t（1；17）（q42；q21）	IRF2BP2::RARA	7例	敏感	无数据	[5]
t（2；17）（q32；q21）	NABP1::RARA	1例	不确定	无数据	[5]
t（3；17）（q26；q21）	FNDC3B::RARA	1例	不确定	无数据	[9]
t（3；14；17）（q12；q11；q21）	TFG::RARA	1例	敏感	无数据	[5]
t（3；17）（q26；q21）	TBLR1::RARA	4例	不敏感	敏感	[5]
t（4；17）（q12；q21）	FIP1L1::RARA	5例	敏感	无数据	[9]
t（5；17）（q35；q21）	NPM1::RARA	>10例	敏感	无数据	[5]
t（7；17）（q11；q21）	GTF2I::RARA	1例	抵抗	抵抗	[9]
t（7；17）（p22；q21）	TNRC18::RARA	2例	抵抗	抵抗	[15-16]
t（11；17）（q23；q21）	ZBTB16::RARA	>30例	抵抗	抵抗	[18]
t（11；17）（q13；q21）	NUMA::RARA	1例	敏感	无数据	[9]
无	NUP98::RARA	1例	无数据	无数据	[21]
t（14；17）（q11；q21）	HNRNPC::RARA	1例	抵抗	无数据	[22]
t（15；17）（q22；q21）	PML::RARA	>98%	敏感	敏感	[5]
t（X；17）（p11；q21）	BCOR::RARA	3例	敏感	抵抗	[9]
t（17；17）（q21；q24）	PRKAR1A::RARA	1例	不确定	不确定	[24]
t（17；17）（q21；q21）	STAT3::RARA	3例	抵抗	抵抗	[25]
t（17；17）（q21；q21）	STAT5B::RARA	>10例	抵抗	抵抗	[27]

融合染色体	融合基因	变异型APL发生情况	对ATRA的反应	对ATO的反应	参考文献
t（1；17）（q42；q21）	IRF2BP2::RARA	7例	敏感	无数据	[5]
t（2；17）（q32；q21）	NABP1::RARA	1例	不确定	无数据	[5]
t（3；17）（q26；q21）	FNDC3B::RARA	1例	不确定	无数据	[9]
t（3；14；17）（q12；q11；q21）	TFG::RARA	1例	敏感	无数据	[5]
t（3；17）（q26；q21）	TBLR1::RARA	4例	不敏感	敏感	[5]
t（4；17）（q12；q21）	FIP1L1::RARA	5例	敏感	无数据	[9]
t（5；17）（q35；q21）	NPM1::RARA	>10例	敏感	无数据	[5]
t（7；17）（q11；q21）	GTF2I::RARA	1例	抵抗	抵抗	[9]
t（7；17）（p22；q21）	TNRC18::RARA	2例	抵抗	抵抗	[15-16]
t（11；17）（q23；q21）	ZBTB16::RARA	>30例	抵抗	抵抗	[18]
t（11；17）（q13；q21）	NUMA::RARA	1例	敏感	无数据	[9]
无	NUP98::RARA	1例	无数据	无数据	[21]
t（14；17）（q11；q21）	HNRNPC::RARA	1例	抵抗	无数据	[22]
t（15；17）（q22；q21）	PML::RARA	>98%	敏感	敏感	[5]
t（X；17）（p11；q21）	BCOR::RARA	3例	敏感	抵抗	[9]
t（17；17）（q21；q24）	PRKAR1A::RARA	1例	不确定	不确定	[24]
t（17；17）（q21；q21）	STAT3::RARA	3例	抵抗	抵抗	[25]
t（17；17）（q21；q21）	STAT5B::RARA	>10例	抵抗	抵抗	[27]