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Cytogenetics and Molecular Genetics

Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19

Abstract

Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 × 109/l), 15 showed hemoglobin8 g/dl and 14 showed platelet count 100 × 109/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.

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References

  1. Mundy GR, Ibbotson KJ, D'Souza SM, Simpson EL, Jacobs JW, Martin TJ . The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med 1984; 310: 1718–1727.

    Article  CAS  Google Scholar 

  2. McKay C, Furman WL . Hypercalcemia complicating childhood malignancies. Cancer 1993; 72: 256–260.

    Article  CAS  Google Scholar 

  3. Rheingold SR, Lange BJ . Supportive care of children with cancer: Oncology emergencies: Hypercalcemia. In: Pizzo PA and Poplack DG (eds). Principles and Practice of Pediatric Oncology, 4th edn. Williams & Wilkins, 2002, pp 1197–1198.

    Google Scholar 

  4. Seymour JF, Gagel RF . Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993; 82: 1383–1394.

    CAS  PubMed  Google Scholar 

  5. Burtis WJ, Brady TG, Orloff JJ, Ersbak JB, Warrell Jr RP, Olson BR et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990; 322: 1106–1112.

    Article  CAS  Google Scholar 

  6. Akatsu T, Takahashi N, Udagawa N, Sato K, Nagata N, Moseley JM et al. Parathyroid hormone (PTH)-related protein is a potent stimulator of osteoclast-like multinucleated cell formation to the same extent as PTH in mouse marrow cultures. Endocrinology 1989; 125: 20–27.

    Article  CAS  Google Scholar 

  7. Harutsumi M, Akazai A, Kitamura T, Manki A, Tanaka H, Oda M et al. A case of acute lymphoblastic leukemia accompanied with the production of parathyroid hormone-related protein. Miner Electrolyte Metab 1995; 21: 171–176.

    CAS  PubMed  Google Scholar 

  8. Hibi S, Funaki H, Ochiai-Kanai R, Ikushima S, Todo S, Sawada T et al. Hypercalcemia in children presenting with acute lymphoblastic leukemia. Int J Hematol 1997; 66: 353–357.

    Article  CAS  Google Scholar 

  9. Shimonodan H, Nagayama J, Nagatoshi Y, Hatanaka M, Takada A, Iguchi H et al. Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast-producing parathyroid hormone-related peptide: a case report and review of the literature. Pediatr Blood Cancer 2005; 45: 333–339.

    Article  Google Scholar 

  10. Inaba T, Roberts WM, Shapiro LH, Jolly KM, 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 

  11. Hunger SP, Ohyashiki K, Toyama K, Cleary ML . Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Genes Dev 1992; 6: 1608–1620.

    Article  CAS  Google Scholar 

  12. Look AT . Oncogenic transcription factors in the human acute leukemias. Science 1997; 278: 1059–1064.

    Article  CAS  Google Scholar 

  13. Hunger SP . Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 1996; 87: 1211–1224.

    CAS  Google Scholar 

  14. Devaraj PE, Foroni L, Sekhar M, Butler T, Wright F, Mehta A et al. E2A/HLF fusion cDNAs and the use of RT-PCR for the detection of minimal residual disease in t(17;19)(q22;p13) acute lymphoblastic leukemia. Leukemia 1994; 8: 1131–1138.

    CAS  PubMed  Google Scholar 

  15. Takahashi H, Goto H, Funabiki T, Fujii H, Yamazaki S, Fujioka K et al. Expression of two types of E2A-HLF fusion proteins in YCUB-2, a novel cell line established from B-lineage leukemia with t(17;19). Leukemia 2001; 15: 995–997.

    Article  CAS  Google Scholar 

  16. Matsunaga T, Inaba T, Matsui H, Okuya M, Miyajima A, Inukai T et al. Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Blood 2004; 103: 3185–3191.

    Article  CAS  Google Scholar 

  17. Yoshihara T, Inaba T, Shapiro LH, Kato JY, Look AT . E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF. Mol Cell Biol 1995; 15: 3247–3255.

    Article  CAS  Google Scholar 

  18. Inukai T, Inaba T, Yoshihara T, Look AT . Cell transformation mediated by homodimeric E2A-HLF transcription factors. Mol Cell Biol 1997; 17: 1417–1424.

    Article  CAS  Google Scholar 

  19. Inaba T, Inukai T, Yoshihara T, Seyschab H, Ashmun RA, Canman CE et al. Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. Nature 1996; 382: 541–544.

    Article  CAS  Google Scholar 

  20. Inukai T, Inaba T, Ikushima S, Look AT . The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Mol Cell Biol 1998; 18: 6035–6043.

    Article  CAS  Google Scholar 

  21. Inukai T, Inaba T, Dang J, Kuribara R, Ozawa K, Miyajima A et al. TEF, an antiapoptotic bZIP transcription factor related to the oncogenic E2A-HLF chimera, inhibits cell growth by down-regulating expression of the common beta chain of cytokine receptors. Blood 2005; 105: 4437–4444.

    Article  CAS  Google Scholar 

  22. Smith KS, Rhee JW, Naumovski L, Cleary ML . Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice. Mol Cell Biol 1999; 19: 4443–4451.

    Article  CAS  Google Scholar 

  23. Honda H, Inaba T, Suzuki T, Oda H, Ebihara Y, Tsuiji K et al. Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia. Blood 1999; 93: 2780–2790.

    CAS  PubMed  Google Scholar 

  24. Hunger SP, Devaraj PE, Foroni L, Secker-Walker LM, Cleary ML . Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL. Blood 1994; 83: 2970–2977.

    CAS  PubMed  Google Scholar 

  25. Tsuchida M, Ikuta K, Hanada R, Saito T, Isoyama K, Sugita K et al. Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995. Leukemia 2000; 14: 2295–2306.

    Article  CAS  Google Scholar 

  26. Yamaguchi K, Kiyokawa T, Watanabe T, Ideta T, Asayama K, Mochizuki M et al. Increased serum levels of C-terminal parathyroid hormone-related protein in different diseases associated with HTLV-1 infection. Leukemia 1994; 8: 1708–1711.

    CAS  PubMed  Google Scholar 

  27. Kurosawa H, Goi K, Inukai T, Chang KS, Shinjyo T, Rakestraw KM et al. Two candidate downstream target genes for E2A-HLF. Blood 1999; 93: 321–332.

    CAS  PubMed  Google Scholar 

  28. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA 1993; 90: 11924–11928.

    Article  CAS  Google Scholar 

  29. Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA . Proinflammatory cytokine (TNFalpha/IL-1alpha) induction of human osteoclast formation. J Pathol 2002; 198: 220–227.

    Article  CAS  Google Scholar 

  30. Niizuma H, Fujii K, Sato A, Fujiwara I, Takeyama J, Imaizumi M . PTHrP-independent hypercalcemia with increased proinflammatory cytokines and bone resorption in two children with CD19-negative precursor B acute lymphoblastic leukemia. Pediatr Blood Cancer 2006, (E-pub aheadof print).

  31. Gurney H, Grill V, Martin TJ . Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. Lancet 1993; 341: 1611–1613.

    Article  CAS  Google Scholar 

  32. Young G, Shende A . Use of pamidronate in the management of acute cancer-related hypercalcemia in children. Med Pediatr Oncol 1998; 30: 117–121.

    Article  Google Scholar 

  33. Lteif AN, Zimmerman D . Bisphosphonates for treatment of childhood hypercalcemia. Pediatrics 1998; 102: 990–993.

    Article  CAS  Google Scholar 

  34. Daheron L, Brizard F, Millot F, Cividin M, Lacotte L, Guilhot F et al. E2A/HLF fusion gene in an acute lymphoblastic leukemia patient with disseminated intravascular coagulation and a normal karyotype. Hematol J 2002; 3: 153–156.

    Article  Google Scholar 

  35. Yeung J, Kempski H, Neat M, Bailey S, Smith O, Brady HJ . Characterization of the t(17;19) translocation by gene-specific fluorescent in situ hybridization-based cytogenetics and detection of the E2A-HLF fusion transcript and protein in patients' cells. Haematologica 2006; 91: 422–424.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Masahiro Tsuchida (Department of Pediatrics, Ibaraki Children's Hospital, Mito, Japan) for providing the clinical data of TCCSG and Keiko Kagami (Department of Pediatrics, University of Yamanashi, School of Medicine) for technical supports.

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Inukai, T., Hirose, K., Inaba, T. et al. Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 21, 288–296 (2007). https://doi.org/10.1038/sj.leu.2404496

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