ETP-ALL实验室诊断和治疗新进展

doi:10.3969/j.issn.1673-8640.2025.01.001

摘要/Abstract

摘要：

早期前体T淋巴细胞（ETP）是起源于骨髓并定植于胸腺的最早的祖细胞，急性早期前体T淋巴细胞白血病（ETP-ALL）是因研究技术的进步被发现的急性T淋巴细胞白血病（T-ALL）的新亚型。传统的血细胞发育观认为，造血细胞遵循从多能干细胞到谱系限制的祖细胞谱系发育的基本过程，造血过程中的第1个谱系发育过程分为共同的髓系和淋巴系，T淋巴细胞谱系限制的最后步骤发生在胸腺。然而，ETP-ALL既具有T细胞和B细胞的分化潜能，也具有髓系细胞分化潜能，这对传统的造血谱系发育规律提出了挑战。ETP-ALL的谱系来源和分化潜能尚不明确，其免疫表型、基因特征，以及诊断和治疗均处于探索阶段，增加了诊断和鉴别诊断的难度。目前，基于流式细胞免疫分型技术的评分系统是诊断ETP-ALL的重要辅助依据。ETP-ALL治疗通常包括诱导治疗、缓解后的巩固强化治疗和维持治疗，但患者对常规化疗方案反应较差，缓解后复发率较高。完全缓解后，符合条件的患者宜尽早进行异基因造血干细胞（HSC）移植。文章就ETP-ALL的起源和调控，以及ETP-ALL实验室诊断和临床治疗的新进展进行综述，以期为ETP-ALL的诊断和治疗提供帮助。

关键词: 急性早期前体T淋巴细胞白血病, 早期前体T淋巴细胞, 混合表型急性白血病

Abstract:

Early T-cell precursors （ETP） are the earliest progenitors that originate from the bone marrow and reside in the thymus. Early T-cell precursor acute lymphoblastic leukemia （ETP-ALL） is a new subtype of T-cell acute lymphoblastic leukemia （T-ALL） that is discovered with the advancement of research techniques. The traditional view of hematopoiesis is that hematopoietic cells follow a basic process of lineage commitment from multipotent stem cells to lineage-restricted progenitor cells. The first step of hematopoiesis is common myeloid and lymphoid differentiation pathways，and the final step of T lymphocyte lineage restriction occurs in the thymus. However，ETP-ALL has differential potential of T，B and myeloid cells，challenging the traditional hematopoietic lineage development rules. At present，the lineage origin and differential potential of ETP-ALL can not be clearly identified，so its immune phenotype，genetic characteristics and diagnosis and treatment are being investigated，which also increases the difficulty of diagnosis and differential diagnosis. Currently，the flow cytometry immuno-phenotyping scoring system is an important auxiliary diagnostic method of ETP-ALL. ETP-ALL treatment typically includes induction therapy，consolidation therapy after remission and maintenance therapy. Due to poor response to conventional chemotherapy and high relapse rate after remission，patients who achieve complete remission and meet the criteria should perform allogeneic hematopoietic stem cell transplantation as soon as possible. This review provides an overview of the origin and regulation of ETP-ALL，as well as the latest advances in the laboratory diagnosis and clinical treatment of ETP-ALL，which may be useful for its diagnosis and treatment.

Key words: Early T-cell precursor acute lymphoblastic leukemia, Early T-cell precursor, Mixed phenotype leukemia

中图分类号:

R733.71

刘梦娜, 王洪玲, 白萍, 蔡宇, 李莉. ETP-ALL实验室诊断和治疗新进展[J]. 检验医学, 2025, 40(1): 1-7.

LIU Mengna, WANG Hongling, BAI Ping, CAI Yu, LI Li. Research progress on laboratory diagnosis and treatment of ETP-ALL[J]. Laboratory Medicine, 2025, 40(1): 1-7.

图/表 1

参考文献 45

[1]	ARBER D A, ORAZI A, HASSERJIAN R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J]. Blood, 2016, 127(20):2391-2405. DOI PMID
[2]	COUSTAN-SMITH E, MULLIGHAN C G, ONCIU M, et al. Early T-cell precursor leukaemia:a subtype of very high-risk acute lymphoblastic leukaemia[J]. Lancet Oncol, 2009, 10(2):147-156.
[3]	CONTER V, VALSECCHI M G, BULDINI B, et al. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols:a retrospective analysis[J]. Lancet Haematol, 2016, 3(2):e80-6.
[4]	JAIN N, LAMB A V,O'BRIEN S,et al. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL)in adolescents and adults:a high-risk subtype[J]. Blood, 2016, 127(15):1863-1869.
[5]	NEUMANN M, COSKUN E, FRANSECKY L, et al. FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors[J]. PLoS One, 2013, 8(1):e53190.
[6]	KOCH U, RADTKE F. Mechanisms of T cell development and transformation[J]. Annu Rev Cell Dev Biol, 2011, 27:539-562. DOI PMID
[7]	公彦栋. 单细胞精度解析人类T淋巴细胞起源及胸腺器官发生[D]. 北京: 中国人民解放军军事科学院, 2020.
[8]	LUC S, LUIS T C, BOUKARABILA H, et al. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential[J]. Nat Immunol, 2012, 13(4):412-419. DOI PMID
[9]	BELL J J, BHANDOOLA A. The earliest thymic progenitors for T cells possess myeloid lineage potential[J]. Nature, 2008, 452(7188):764-767.
[10]	SAMBANDAM A, MAILLARD I, ZEDIAK V P, et al. Notch signaling controls the generation and differentiation of early T lineage progenitors[J]. Nat Immunol, 2005, 6(7):663-670. PMID
[11]	SCHLENNER S M, MADAN V, BUSCH K, et al. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus[J]. Immunity, 2010, 32(3):426-436. DOI PMID
[12]	PAIVA R A, RAMOS C V, LEIRIA G, et al. IL-7 receptor drives early T lineage progenitor expansion[J]. J Immunol, 2022, 209(10):1942-1949. DOI PMID
[13]	YE M T, WANG Y, ZUO Z, et al. Integrated clinical genotype-phenotype characteristics of early T-cell precursor acute lymphoblastic leukemia[J]. Cancer, 2023, 129(1):49-59.
[14]	CHANDRA D, SINGH M K, GUPTA R, et al. Clinicopathological and immunophenotypic features of early T cell precursor acute lymphoblastic leukaemia:a flow cytometry score for the initial diagnosis[J]. Int J Lab Hematol, 2021, 43(6):1417-1423.
[15]	RAHMAN K, SINGH P, CHANDRA D, et al. Early T-cell precursor acute lymphoblastic leukemia with Auer rods-a case report[J]. Int J Lab Hematol, 2020, 42(1):e27-e29.
[16]	GAJENDRA S, SACHDEV R, DORWAL P, et al. Mixed-phenotypic acute leukemia:cytochemically myeloid and phenotypically early T-cell precursor acute lymphoblastic leukemia[J]. Blood Res, 2014, 49(3):196-198.
[17]	MARBALLI BASAVARAJU D, MISHRA S, CHHABRA G, et al. Comparison of flowcytometry-based scoring system for the diagnosis of early T precursor-acute lymphoblastic leukemia[J]. Cytometry B Clin Cytom, 2023, 104(6):453-459.
[18]	KHOGEER H, RAHMAN H, JAIN N, et al. Early T precursor acute lymphoblastic leukaemia/lymphoma shows differential immunophenotypic characteristics including frequent CD33 expression and in vitro response to targeted CD33 therapy[J]. Br J Haematol, 2019, 186(4):538-548.
[19]	YOON J H, KIM H S, MIN G J, et al. Cytogenetic and molecular characteristics and outcomes of adult patients with early T-cell precursor acute lymphoblastic leukemia[J]. Eur J Haematol, 2023, 110(2):137-148.
[20]	KRISHNAN Y, S G, JOY A, et al. Childhood early T cell precursor acute lymphoblastic leukaemia with t(12;17)(p13;q21)translocation - a rare entity or part of ETP/myeloid mixed phenotype acute leukaemia[J]. Gulf J Oncolog, 2022, 1(40):78-82.
[21]	KAWASHIMA-GOTO S, IMAMURA T, TOMOYASU C, et al. BCL2 inhibitor (ABT-737):a restorer of prednisolone sensitivity in early T-cell precursor-acute lymphoblastic leukemia with high MEF2C expression?[J]. PLoS One, 2015, 10(7):e132926.
[22]	BALDUS C D, TANNER S M, RUPPERT A S, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics:a cancer and leukemia group B study[J]. Blood, 2003, 102(5):1613-1618.
[23]	HEESCH S, SCHLEE C, NEUMANN M, et al. BAALC-associated gene expression profiles define IGFBP7 as a novel molecular marker in acute leukemia[J]. Leukemia, 2010, 24(8):1429-1436.
[24]	FANG H, WANG W, EL HUSSEIN S, et al. B-cell lymphoma/leukaemia 11B(BCL11B)expression status helps distinguish early T-cell precursor acute lymphoblastic leukaemia/lymphoma(ETP-ALL/LBL)from other subtypes of T-cell ALL/LBL[J]. Br J Haematol, 2021, 194(6):1034-1038.
[25]	LU B Y, THANAWALA S U, ZOCHOWSKI K C, et al. Decitabine enhances chemosensitivity of early T-cell precursor-acute lymphoblastic leukemia cell lines and patient-derived samples[J]. Leuk Lymphoma, 2016, 57(8):1938-1941.
[26]	FRANSECKY L, NEUMANN M, HEESCH S, et al. Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL[J]. J Hematol Oncol, 2016, 9(1):95.
[27]	ZHANG J, DING L, HOLMFELDT L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia[J]. Nature, 2012, 481(7380):157-163.
[28]	XIAO J, CAI Z, WANG H, et al. The clinical characteristics and prognosis of AYA and older adult ETP-ALL/LBL:a real-world multicenter study in China[J]. Front Oncol, 2022, 12:846573.
[29]	ZUURBIER L, GUTIERREZ A, MULLIGHAN C G, et al. Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors[J]. Haematologica, 2014, 99(1):94-102.
[30]	ALEXANDER T B, GU Z, IACOBUCCI I, et al. The genetic basis and cell of origin of mixed phenotype acute leukaemia[J]. Nature, 2018, 562(7727):373-379.
[31]	NEUMANN M, HEESCH S, GÖKBUGET N, et al. Clinical and molecular characterization of early T-cell precursor leukemia:a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations[J]. Blood Cancer J, 2012, 2(1):e55.
[32]	NEUMANN M, HEESCH S, SCHLEE C, et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations[J]. Blood, 2013, 121(23):4749-4752.
[33]	LO NIGRO L, ANDRIANO N, BULDINI B, et al. FLT3-ITD in children with early T-cell precursor (ETP)acute lymphoblastic leukemia:incidence and potential target for monitoring minimal residual disease(MRD)[J]. Cancers (Basel), 2022, 14(10):2475.
[34]	NORONHA E P, MARQUES L V C, ANDRADE F G, et al. T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with NOTCH1 mutation as a good prognostic factor[J]. Cancer Manag Res, 2019, 11:3933-3943.
[35]	TARIQ H, SHETTY S. Emerging necessity of myeloid mutational analysis in early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL)[J]. Turk J Haematol, 2023, 40(3):227-229.
[36]	XUE S L, WU D P, SUN A N, et al. CAG regimen enables relapsed or refractory T-cell acute lymphocytic leukemia patients to achieve complete remission:a report of six cases[J]. Am J Hematol, 2008, 83(2):167-170.
[37]	QIAN J J, HU X, WANG Y, et al. CAG regimen for refractory or relapsed adult T-cell acute lymphoblastic leukemia:a retrospective,multicenter,cohort study[J]. Cancer Med, 2020, 9(15):5327-5334.
[38]	BHATLA T, WANG J, MORRISON D J, et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia[J]. Blood, 2012, 119(22):5201-5210. DOI PMID
[39]	MENG T, YAO Y, XU Y, et al. Salvage therapy with decitabine in combination with granulocyte colony-stimulating factor,low-dose cytarabine,and aclarubicin in patients with refractory or relapsed early T-cell precursor acute lymphoblastic leukemia[J]. Hematol Oncol, 2020, 38(5):834-837.
[40]	BORAH P, DAYAL N, PATHAK S, et al. Short-course venetoclax with standard chemotherapy is effective in early T-cell precursor acute lymphoblastic leukemia[J]. J Pediatr Hematol Oncol, 2023, 45(5):271-274. DOI PMID
[41]	NUMAN Y, ALFAYEZ M, MAITI A, et al. First report of clinical response to venetoclax in early T-cell precursor acute lymphoblastic leukemia[J]. JCO Precis Oncol, 2018, 2:127.
[42]	ARORA S, VACHHANI P, BACHIASHVILI K, et al. Venetoclax with chemotherapy in relapse/refractory early T-cell precursor acute lymphoblastic leukemia[J]. Leuk Lymphoma, 2021, 62(9):2292-2294.
[43]	TREMBLAY C S, SAW J, BOYLE J A, et al. STAT5 activation promotes progression and chemotherapy resistance in early T-cell precursor acute lymphoblastic leukemia[J]. Blood, 2023, 142(3):274-289.
[44]	MAUDE S L, DOLAI S, DELGADO-MARTIN C, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP)acute lymphoblastic leukemia[J]. Blood, 2015, 125(11):1759-1767.
[45]	BATALLER A, GARROTE M, OLIVER-CALDÉS A, et al. Early T-cell precursor lymphoblastic leukaemia:response to FLAG-IDA and high-dose cytarabine with sorafenib after initial refractoriness[J]. Br J Haematol, 2019, 185(4):755-757.

抗体名称	5抗体标记			6抗体标记		6抗体（1a）标记		7抗体标记
抗体名称	-1分	0分	1分	-1分	1分	-1分	1分	-2分	0分	2分
CD5	≥75%		<75%	≥75%	<75%	≥5%	<5%	≥75%		<75%
CD8	≥5%		<5%	≥5%	<5%	≥5%	<5%	≥5%		<5%
CD13		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
CD33		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
CD34		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
HLA-DR					≥25%		≥25%		≥25%	≥75%
CD117									≥25%	≥75%

抗体名称	5抗体标记			6抗体标记		6抗体（1a）标记		7抗体标记
抗体名称	-1分	0分	1分	-1分	1分	-1分	1分	-2分	0分	2分
CD5	≥75%		<75%	≥75%	<75%	≥5%	<5%	≥75%		<75%
CD8	≥5%		<5%	≥5%	<5%	≥5%	<5%	≥5%		<5%
CD13		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
CD33		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
CD34		<20%	≥20%		≥25%		≥25%		≥25%	≥75%
HLA-DR					≥25%		≥25%		≥25%	≥75%
CD117									≥25%	≥75%