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The higher expression of α and β isoforms of the human glucocorticoid receptor in leukemic B-progenitors compared to normal CD10+ BM cells does not correlate with methylprednisolone-induced apoptosis

Leukemia volume 18, pages 890–892 (2004)Cite this article

TO THE EDITOR

Initial response to glucocorticoid (GC) treatment is an important prognostic factor in childhood acute lymphoblastic leukemia (ALL).1 However, the molecular basis underlying GC action in ALL is controversial. The intracellular effects of GC are mediated by human glucocorticoid receptors (hGR), which once activated by ligand binding migrate to the nucleus, where they may act as positive or negative transcription regulators. Activated hGR mono/homodimers recognize and interact with glucocorticoid-responsive elements (GRE) located in the promoter region of different genes. Moreover, hGR may also interact with important transcriptional factors such as activator protein-1 (AP-1) and nuclear factor κB (NFκB),2 which are transrepressed. Different hGR isoforms have been identified: hGRα, hGRβ, hGRγ, hGR-A and hGR-P, of which hGRα is thought to be the primary mediator of glucocorticoid action, whereas in the other isoforms the ligand-binding (hGRβ, hGR-P) or the DNA-binding domain (hGR-A, hGRγ) is disrupted. hGRβ is generated by the alternative splicing of the ninth exon at the 3′ end of the GR gene, and the resulting protein differs by only the 15 carboxy-terminal amino acids. As hGRβ lacks the ligand-binding domain, it is unable to modulate the expression of GC-responsive genes, and is thought to be a dominant-negative modulator of the hGRα isoform. In fact, hGRβ was able to disrupt the hGRα-dependent activation of a MMTV-luciferase construct in COS-7 cells.3 Reduced hGRα/hGRβ ratio, due to decreased α and increased β isoforms expression, was reported in a GC-resistant chronic lymphocytic leukemia (CLL) case.4 In ALL, the T-lineage blasts are more resistant to GC and express lower hGRα/hGRβ ratio than the B-lineage ones, mainly due to the lower expression of hGRα. Compared to normal lymphocytes, pre-B ALL cells presented similar hGRα/hGRβ ratios, despite the significant lower expression of hGRα.5 However, the only study quantifying hGRα and hGRβ protein levels compared leukemic lymphoid cells to EBV-transformed lymphocytes. Moreover, only eight pre-B ALL cases were analyzed.5 We therefore compared the hGRβ, hGRα and hGR protein levels in B-progenitors from ALL of the common subtype (cALL) with their normal bone marrow (BM) CD10+ counterparts. In addition, the in vitro sensitivity to methylprednisolone-induced apoptosis was determined.

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Authors and Affiliations

  1. Hematology Division, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    L M M Albuquerque, A B Garcia, R P Falcão & E M Rego

  2. Fiocruz, Salvador, Brazil

    J O Mengel

  3. Endocrinology Division, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    M de Castro

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  1. L M M Albuquerque
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Correspondence to E M Rego.

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Albuquerque, L., Garcia, A., Mengel, J. et al. The higher expression of α and β isoforms of the human glucocorticoid receptor in leukemic B-progenitors compared to normal CD10+ BM cells does not correlate with methylprednisolone-induced apoptosis. Leukemia 18, 890–892 (2004). https://doi.org/10.1038/sj.leu.2403318

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