The lincRNAHOTAIRM1, located in theHOXAgenomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature

Abstract

Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown.We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients.The lowest expression level was observed in acute promyelocytic leukemia (P < 0.001) and the highest in t(6;9) AML (P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04;P = 0.001), shorter leukemia-free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1-mutated AML (P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33- microRNA signature that included miR-196b (P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR-196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004).Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature.

PU.1 controls the expression of long noncoding RNA hotairm1 during granulocytic differentiation

“…The data represent the mean of three replicates ± SD. *p < 0.05; **p < 0.01; ***p < 0.001 patients [10]. Similarly, PU.1 was also lower in APL, supporting the above cell line-based results.…”

Long non-coding RNAs in normal and malignant hematopoiesis

“…As discussed above, HOTAIRM1, a lncRNA transcribed antisense to the HOXA genes, has been suggested to play a role in myelopoiesis [27, 37]. Notably, HOTAIRM1 was also found upregulated in a large series of AML patients with intermediate-risk cytogenetics, in particular in patients with NPM1 mutation, showing an independent negative prognostic value [69]. These findings suggest a role of HOX genes in the context of AML with NPM1 mutations.…”

Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs

“…Another lncRNA showing at least a clinical indication to therapeutic resistance is Hox antisense intergenic RNA myeloid 1 (HOTAIRM1). In an analysis of 241 AML patient specimens, increased levels of HOTAIRM1 were observed and correlated with shorter OS, shorter leukemia-free survival and a higher cumulative incidence of relapse in uni- and multivariate analyses [48]. Again, functional experiments further proving that therapeutic resistance is indeed mediated via HOTAIRM1 will be needed to further clarify the role of HOTAIRM1 in this respect.…”