Abstract
The most frequent targets of genetic alterations in human leukemias are transcription factor genes with essential functions in normal blood cell development. The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas. Very few studies have reported an association of IRF4 with childhood malignancy, whereas high transcript levels have been observed in the more mature immunophenotype of ALL. Our aim was to investigate the expression levels of IRF4 in the diagnostic samples of pediatric leukemias and compare them to those of healthy controls, in order to determine aberrant gene expression and whether it extends to leukemic subtypes other than the relatively mature ALL subpopulation. Quantitative real-time RT-PCR methodology was used to investigate IRF4 expression in 58 children with acute leukemias, 4 leukemic cell lines and 20 healthy children. We show that aberrant IRF4 gene expression is implicated in a variety of leukemic subtypes; higher transcript levels appear in the more immature B-common ALL subtype and in T-cell than in B-cell leukemias, with the highest expression levels appearing in the AML group. Interestingly, we show that childhood leukemia, irrespective of subtype or cell maturation stage, is characterised by a minimum of approximately twice the amount of IRF4 gene expression encountered in healthy children. A statistically significant correlation also appeared to exist between high IRF4 expression and relapse. Our results show that ectopic expression of IRF4 follows the reverse expression pattern of what is encountered in normal B-cell development and that there might be a dose-dependency of childhood leukemia for aberrantly expressed IRF4, a characteristic that could be explored therapeutically. It is also suggested that high IRF4 expression might be used as an additional prognostic marker of relapse at diagnosis.
Highlights
Acute leukemia (AL) is regarded the most common type of malignancy in children
The gene was found up-regulated in a broader spectrum of leukemic subtypes and maturation stages than previously thought, with the highest transcript levels appearing in the acute myeloid leukemia (AML) group (Figure 1)
The 3 cell lines, despite being phenotypically distant from differentiated cells, appeared to express even higher levels of the gene than the patients; this possibly implies that in childhood leukemia, Interferon Regulatory Factor 4 (IRF4) gene expression is not subject to the feedback regulation mechanisms that operate in normal tissues
Summary
Despite the good overall response of childhood patients to current chemotherapeutic treatments and the long-term event-free survival rates exceeding 80% [1,2], a significant percentage of the population show resistance to therapy and/or relapse, often with devastating consequences. This has highlighted the importance of devising new therapies that will target the resistant clones and increase overall survival. It has already been demonstrated that a subset of genes expressed in normal HSCs are highly reactivated in leukemic stem cells (LSCs), indicating that the LSCs express the self-renewal-associated programme normally characterising the HSCs [3]. The identification of specific genetic aberrations that characterise leukemic cells, such as abnormal gene expression, can lead to a better understanding of what constitutes their unlimited self-renewing properties and subsequently reveal potential molecular targets for successful therapy
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