Implications of lipocalin 2 expression in acute myeloid leukemia

Therapeutic success and prognosis of patients with acute myeloid leukemia (AML) largely depend on a variety of patient- and disease-specific characteristics. For over 20 years the recurrent chromosomal aberrations, noted in approximately 55% of newly diagnosed AML patients, were the most robust and powerful prognostic indicators, separating patients into “favorable” [core binding factor (CBF) leukemias, t(15;17)], “intermediate” (including normal karyotype, + 8) and “poor” [5q−/− 5, 7q−/− 7, 17p−, inv(3), t(3;3), complex karyotype and others] prognostic categories [1–4]. In recent years, discoveries in the field have led to a more refined risk stratification of the established cytogenetic groups. For example, the presence of c-kit mutation in CBF leukemias is associated with a higher rate of relapse and lower disease-free (DFS) and overall survival (OS) as compared to those with kit-wild CBF-AML [5]. Also, expression of a monosomal karyotype, defined by either the presence of at least two monosomies or a monosomy with other structural chromosomal abnormalities, carries a particularly grave prognosis, with an OS of less than 5% [6,7]. Although genetic alterations leading to MLL gene rearrangements are indicative of high-risk disease, a subgroup of patients carrying t(9;11)(p21;q23) have an OS of 40%, which is comparable to that of an intermediate-risk group [8].

Recently, much scientific attention has been paid to the cytogenetically normal (CN), yet clinically heterogeneous, AML population. Molecular analysis of this group has shown that the majority of patients with CN-AML have detectable recurrent genetic aberrations involving NPM1, CEBPα, FLT3-ITD, TET2, DNMT3A, IDH1/IDH2 and others [9,10]. In fact, evaluating the presence of NPM1, FLT3-ITD and CEBPα mutations at diagnosis in patients with CN-AML has became standard clinical practice at many centers, as these molecular markers alone and/or in combination are powerful predictors of outcome [11]. Recently published 18 gene panel mutational profiling in patients with AML suggests that it could be used not only to further enhance the risk stratification, but also to influence the selection of therapy [12]. In addition to the rapidly expanding field of molecular characterization of AML, other markers have recently been identified. For example, CD25 expression in AML demonstrated prognostic relevance irrespective of established biomarkers [13].

In the current issue of Leukemia and Lymphoma, Yang et al. [14] have evaluated the prognostic relevance of lipocalin 2 (Lcn2) in patients with AML. Lcn2 is a glycoprotein secreted by macrophages and neutrophils, as well as epithelial and tumor cells [15]. It belongs to a family of proteins known to transport small lipophilic ligands such as retinoic acid, prostaglandins and others [15]. Lcn2 has been studied as a potential biomarker of various processes and diseases, including malignancies [16]. Previous studies have shown that in patients with endometrial cancer, increased Lcn2 expression is associated with aggressive tumor behavior, the presence of distant metastases and reduced survival [17]. A variety of in vitro animal model and human studies have demonstrated that Lcn2 promotes breast cancer progression by inducing epithelial to mesenchymal transition, and may be a useful biomarker of the disease [18]. Other studies have shown that in patients with chronic myeloid leukemia (CML), Lcn2 expression correlates with the expression of BCR–ABL, and is significantly increased at diagnosis [19]. Notably, Lcn2 secreted by BCR–ABL transformed cells causes apoptosis of normal hematopoietic but not leukemic BCR–ABL+ cells [19].

Yang et al. [14] found that Lcn2 expression was lower in patients with AML as compared with normal controls. They demonstrated that Lcn2 levels appeared to rise and decline with remission and relapse, respectively, in an individual patient, and were not related to the degree of hematopoietic cell maturation [14]. There was no discernible pattern of Lcn2 expression within the AML population. CN-AML and poor-risk AML were found to have similar levels of expression, while AML t(8;21), but not inv(16), demonstrated higher Lcn2 expression [13]. In the univariate analysis, lower Lcn2 expression level was associated with worse OS but had no effect on the leukemia-free survival (LFS) [14]. The only other disease-specific parameter influencing OS was FLT3 status. In multivariate analysis it appeared that Lcn2 high/FLT3-ITD wild type (WT) phenotype resulted in the best OS and LFS [14]. To explain these clinical observations, the authors performed mechanistic studies, the results of which suggest that Lcn2 may act as a pro-apoptotic factor, and its high expression may under certain circumstances increase chemosensitivity [14]. The reported association between Lcn2 expression and survival in AML is novel and intriguing. It will be imperative to confirm the reported findings and to understand the significance of Lcn2 expression in the context of recently reported genetic alterations and other biomarkers. Undoubtedly, it will be a challenge to rationally and optimally integrate this information into the current clinical understanding of AML.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.