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Specific induction of CD33 expression by E2A–HLF: the first evidence for aberrant myeloid antigen expression in ALL by a fusion transcription factor

Leukemia volume 24, pages 865–869 (2010)Cite this article

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Acute lymphoblastic leukemia (ALL) is a clonal expansion of cells committed into the lymphoid lineage, and, thus, ALL cells express cell surface antigens that are present at discrete stages of normal lymphoid precursors. It has been reported that 5–30% of childhood ALLs express so-called myeloid antigens such as CD11b, CD13, CD14, CD15 and CD33.1, 2 As representatively shown in reference no. 1, studies in the early 1990s showed the association of myeloid antigen expression with poor prognosis in childhood ALL. Although subsequent studies, as representatively shown in reference no. 2, failed to confirm the prognostic significance of myeloid antigen expression in childhood ALLs that were treated with intensified chemotherapeutic regimens, a later study by the BFM group showed that expression of CD33, but not other myeloid antigens, was an independent poor prognostic factor for childhood B-precursor ALL.3 The expression of these myeloid antigens on ALL cells has generally been speculated to reflect either misprogramming of differentiation or neoplastic transformation of the particular lymphoid progenitors that co-express myeloid antigens. However, the precise mechanism of myeloid antigen expression in ALL cells largely remains unclarified.

To further clarify the mechanism by which E2A–HLF induces CD33 gene expression, a panel of E2A–HLF mutants (ΔAD1/ΔLH, IF, BX) was tested (Supplementary Figure S3a). Each mutant was expressed in Reh cells induced by Zn at an almost equivalent level to that of intact E2A–HLF in UOC-B1 (Supplementary Figure S3b). EMSA using an oligonucleotide containing the consensus binding sequence of HLF (HLF–CS) as a probe (Supplementary Figure S3c) confirmed the similar DNA-binding activity of ΔAD1/ΔLH, which lacks two transactivation domains of E2A, but has the intact bZIP domain, compared with that of E2A–HLF. However, both the IF mutant, which carries a point mutation leading to amino acid substitution I-532 >F in the bZIP of HLF, equivalent to the mutation in E2A–HLF of HAL-01 cells, and basic region mutant (BX), which contains substitutions of critical amino acids in the basic region of HLF showed reduced binding activities to the HLF–CS probe. Unlike wild-type E2A–HLF, the mRNA level of CD33 was not upregulated by induction of BX, IF, or ΔAD1/ΔLH mutant (Supplementary Figure S3d), indicating that both the DNA-binding and transactivation abilities of E2A–HLF are required for induction of CD33 expression.

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References

  1. Wiersma SR, Ortega J, Sobel E, Weinberg KI . Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia of childhood. N Engl J Med 1991; 324: 800–808.

    Article  CAS  Google Scholar 

  2. Pui CH, Behm FG, Singh B, Rivera GK, Schell MJ, Roberts WM et al. Myeloid-associated antigen expression lacks prognostic value in childhood acute lymphoblastic leukemia treated with intensive multiagent chemotherapy. Blood 1990; 75: 198–202.

    CAS  Google Scholar 

  3. Mejstrikova E, Kalina T, Trka J, Stary J, Hrusak O . Correlation of CD33 with poorer prognosis in childhood ALL implicates a potential of anti-CD33 frontline therapy. Leukemia 2005; 19: 1092–1094.

    Article  CAS  Google Scholar 

  4. Paul SP, Taylor LS, Stansbury EK, McVicar DW . Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2. Blood 2000; 96: 483–490.

    CAS  Google Scholar 

  5. Inukai T, Hirose K, Inaba T, Kurosawa H, Hama A, Inada H et al. Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 2007; 21: 288–296.

    Article  CAS  Google Scholar 

  6. Inaba T, Roberts WM, Shapiro LH, Jolly KW, Raimondi SC, Smith SD et al. Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Science 1992; 257: 531–534.

    Article  CAS  Google Scholar 

  7. Bodger MP, Hart DN . Molecular cloning and functional analysis of the CD33 promotor. Br J Haematol 1998; 102: 986–995.

    Article  CAS  Google Scholar 

  8. van der Velden AHJ, te Marvelde JG, Hoogeveen PG . Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 2001; 97: 3197–3204.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K Nakamura (Hiroshima University, Hiroshima, Japan), Y Nagatoshi (National Kyushu Cancer Center, Fukuoka, Japan), Y Ohtsuka (University of Tokyo, Tokyo, Japan), H Inada (Kurume University School of Medicine, Kurume, Japan), and K Nakamura (Teikyo University, Tokyo, Japan) for providing clinical data of cell surface antigen expression, Wyeth Research (Pearl River, NY, USA) for providing GO, F. Rauscher III (Wister Institute, PA, USA) for providing pMT-CB6+ expression vector, and Y Akahane (Scientific Coordination Group Inc., Saitama, Japan) for sterile splitting of GO.

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Authors and Affiliations

  1. Department of Pediatrics, University of Yamanashi, School of Medicine, Yamanashi, Japan

    K Akahane, T Inukai, X Zhang, K Hirose, I Kuroda, H Honna, K Kagami, K Goi, S Nakazawa & K Sugita

  2. Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    T Inaba

  3. Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan

    H Kurosawa

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    A T Look

  5. Department of Developmental Biology, National Research Institute for Child Health and Development, Tokyo, Japan

    N Kiyokawa & J Fujimoto

  6. Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Japan

    H Goto

  7. Department of Pediatrics, Iwate Medical University School of Medicine, Morioka, Japan. E-mail: tinukai@yamanashi.ac.jp,

    M Endo

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Akahane, K., Inukai, T., Inaba, T. et al. Specific induction of CD33 expression by E2A–HLF: the first evidence for aberrant myeloid antigen expression in ALL by a fusion transcription factor. Leukemia 24, 865–869 (2010). https://doi.org/10.1038/leu.2010.8

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