1 Introduction

To the Editor: Acute myeloid leukemia (AML) and acute leukemia of ambiguous lineage (ALAL) comprise a diverse variety of acute leukemias that are defined by their morphologic, immunophenotypic, and genetic features. AML is characterized by clonal expansion of immature hematopoietic precursors of myeloid lineage in the peripheral blood and bone marrow. AML may arise de novo, evolve from prior myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or after exposure to cytotoxic or radiation therapy, called therapy-related AML [1]. The recent classifications of the World Health Organization (WHO), the 5th Edition Classification of Haematolymphoid Tumours, and the International Consensus Classification of Myeloid and Lymphoid Neoplasms (ICC) both allow for classification of AMLs that arose from, or are otherwise related to, MDS as distinct entities, if diagnostic and exclusionary criteria are met [2, 3]. These subcategories include AML, myelodysplasia-related in the WHO and AML with myelodysplasia-related gene mutations, or AML with myelodysplasia-related cytogenetic abnormalities in the ICC.

Both classifications have moved more toward genetically defined classifications of acute leukemias. Both now recognize MDS-associated mutations as defining of MDS-related AML (AML-MR), a disease with poor prognosis. Among the features that define AML-MR are mutations known as secondary-type or MDS-associated mutations, so named because, in the context of AML, they are highly specific for AML arising from preceding MDS, MPNs, or therapy-related clonal aberrations. The presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 genes is > 95% specific for these “secondary” AMLs [4]. Somatic mutations in RUNX1 are commonly associated with mutations in other genes characterizing AML-MR and are included in this category in the ICC. AML with mutated RUNX1 is a provisional entity in the WHO 4th edition.

ALALs have blast populations that either do not show any clear lineage, acute undifferentiated leukemia (AUL), or those that show multi-lineage differentiation, mixed phenotype acute leukemias (MPAL). ALALs are rare, comprising ~4% of acute leukemias, the majority of those being MPAL [3]. However, leukemias that meet the criteria for other defined categories, such as AMLs with defining genetic abnormalities, are excluded from MPAL. Investigations into the genetic basis of ALAL are limited and have shown great heterogeneity in associated genetic mutations, with some associated with ALL, others with AML, and others with neither. Mutations in MDS-associated genes may be present in a significant proportion of ALAL cases with RUNX1 mutations among the most common [5].

The current classifications are unclear on how ALALs should be classified in the presence of MDS-associated mutations. They suggest excluding leukemias with ambiguous lineage phenotypes that harbor MDS-associated genetic abnormalities from classification under ALAL. However, the clinical and genetic features of ALAL remain poorly characterized, including those with MDS-associated mutations. Our goals for this study are to determine the significance of MDS-associated mutations in ALAL as compared with cases of de novo AML with MDS-associated mutations.

中文翻译：

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与具有 MDS 相关突变的急性髓性白血病相比，具有 MDS 相关突变的模糊谱系的急性白血病显示出相似的预后：来自骨髓病理学组的一项研究

 1 引言

致编者：急性髓系白血病 （AML） 和谱系模糊急性白血病 （ALAL） 包括多种急性白血病，这些白血病由其形态学、免疫表型和遗传特征定义。AML 的特征是外周血和骨髓中髓系的未成熟造血前体克隆扩增。AML可能新发，由既往骨髓增生异常综合征（myelodysgenerative syndrome， MDS）或骨髓增生异常/骨髓增生性肿瘤（myelodysplasy/myeloproliferative neoplasms， MDS/MPN）演变而来，也可能在暴露于细胞毒性或放疗后演变而来，称为治疗相关AML[1]。世界卫生组织 （WHO） 的最新分类、第 5 版血淋巴肿瘤分类以及髓系和淋巴肿瘤国际共识分类 （ICC） 都允许在满足诊断和排除标准的情况下，将由 MDS 引起或以其他方式相关的 AML 分类为不同的实体 [2， 3].这些子类别包括 AML、WHO 中与骨髓增生异常相关的 AML 和具有骨髓增生异常相关基因突变的 AML，或 ICC 中具有骨髓增生异常相关细胞遗传学异常的 AML。

这两种分类都更倾向于遗传定义的急性白血病分类。现在，两者都将 MDS 相关突变定义为 MDS 相关 AML （AML-MR），这是一种预后不良的疾病。定义 AML-MR 的特征包括称为继发型或 MDS 相关突变的突变，之所以这样命名，是因为在 AML 的背景下，它们对由先前 MDS、MPN 或治疗相关克隆畸变引起的 AML 具有高度特异性。SRSF2、SF3B1、U2AF1、ZRSR2、ASXL1、EZH2、BCOR 或 STAG2 基因突变对这些“继发性”AML 的特异性为 > 95% [4]。RUNX1 中的体细胞突变通常与表征 AML-MR 的其他基因突变有关，并在 ICC 中属于这一类别。RUNX1 突变的 AML 是 WHO 第 4 版中的临时实体。

ALAL 的原始细胞群要么不显示任何明确的谱系，即急性未分化白血病 （AUL），要么显示多谱系分化的原始细胞群，即混合表型急性白血病 （MPAL）。ALAL 很少见，占急性白血病的 ~4%，其中大多数是 MPAL [3]。然而，符合其他定义类别标准的白血病，例如具有明确遗传异常的 AML，被排除在 MPAL 之外。对 ALAL 遗传基础的研究是有限的，并且已显示出相关基因突变的巨大异质性，其中一些与 ALL 相关，另一些与 AML 相关，而另一些则两者都没有。MDS 相关基因突变可能存在于 RUNX1 突变的 ALAL 病例中，其中很大一部分是最常见的 [5]。

目前的分类尚不清楚在存在 MDS 相关突变的情况下应如何对 ALAL 进行分类。他们建议将谱系表型不明确且携带 MDS 相关遗传异常的白血病排除在 ALAL 分类之外。然而，ALAL 的临床和遗传特征仍然不清楚，包括那些具有 MDS 相关突变的 ALAL 。我们本研究的目标是确定 ALAL 中 MDS 相关突变与具有 MDS 相关突变的新发 AML 病例相比的显着性。