Abstract
CD44 is a glycoprotein expressed in leucocytes and a marker of leukemia-initiating cells, being shown to be important in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). In this study, we have (i) identified the aberrant antigenic pattern of CD44 and its isoform CD44v6 in T-ALL; (ii) tested the association with different T-cell subtypes and genomic alterations; (iii) identified the impact of CD44 status in T-ALL outcome. Samples from 184 patients (123 T-ALL and 61 AML; <19 years) were analyzed throughout multiparametric flow cytometry. Mutations in N/KRAS, NOTCH1, FBXW7 as well as STIL-TAL1 and TLX3 rearrangements were detected using standard molecular techniques. CD44 expression was characterized in all T-ALL and AML cases. Compared with AML samples in which the median fluorescence intensity (MFI) was 79.1 (1–1272), T-ALL was relatively low, with MFI 43.2 (1.9–1239); CD44v6 expression was rarely found, MFI 1 (0.3-3.7). T-ALL immature subtypes (mCD3/CD1aneg) had a lower CD44 expression, MFI 57.5 (2.7–866.3), whereas mCD3/TCRγδpos cases had higher expressions, MFI 99.9 (16.4–866.3). NOTCH1mut and STIL-TAL1 were associated with low CD44 expression, whereas N/KRASmut and FBXW7mut cases had intermediate expression. In relation to clinical features, CD44 expression was associated with tumor infiltrations (p = 0.065). However, no association was found with initial treatment responses and overall survival prediction. Our results indicate that CD44 is aberrantly expressed in T-ALL being influenced by different genomic alterations. Unraveling this intricate mechanism is required to place CD44 as a therapeutic target in T-ALL.
Highlights
Childhood T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplasm characterized by increased lymphoblast count, mediastinal enlargement, central nervous system infiltration and poor outcome
CD44 phenotype in 30 T cell acute lymphoblastic leukemia (T-ALL) cases was positively associated with increased central nervous system (CNS) and tumor infiltrations [25]
Following the first clinical report on CD44 expression in T-ALL, very few clinical-translational approaches were performed to test the value of CD44 as a marker either in tumor expansion or its relevance in the role of T-ALL outcome
Summary
Childhood T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplasm characterized by increased lymphoblast count, mediastinal enlargement, central nervous system infiltration and poor outcome. With the better understanding of the T-cell development prognostic indicators, the identification of therapeutic targets in T-ALL are being urged to improve prognostic rates [2]. In this context, CD44 is an adhesion glycoprotein widely expressed in hematopoietic cells, binding to hyaluronic acid and other extracellular matrix components, assisting in the homing and anchorage of HSC to their niche [3, 4]. CD44 is expressed in several malignant hematopoietic disorders, including both TALL and acute myeloid leukemia (AML) [7]. Clinically and genetically heterogeneous diseases, T-ALL and AML present overlaps in genetic alterations that lead to pathogenic pathways, such as mutations in genes of the RAS signaling pathway [8], and cellular expression of lineage development markers, such as CD7 expression in AML and CD13 or CD33 in T-ALL [9]
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