PTHrP‐independent hypercalcemia with increased proinflammatory cytokines and bone resorption in two children with CD19‐negative precursor B acute lymphoblastic leukemia

Abstract

Hypercalcemia in childhood acute lymphoblastic leukemia (ALL) is rare and occasionally associated with parathyroid hormone-related protein (PTHrP). However, the pathogenesis of PTHrP-independent hypercalcemia remains unclear. We report two children with precursor B ALL who had marked hypercalcemia (15.8 and 16.6 mg/dl, respectively) and disseminated osteolysis. Serum tumor necrosis factor-alpha (TNF-alpha) and IL-6 were markedly elevated, whereas 1,25(OH)(2) vitamin D(3), intact PTH and PTHrP were decreased or undetected. Analysis of urinary deoxypyridinoline (DPY) or bone biopsy of the osteolytic lesion showed an increased bone resorption, and administration of bisphosphonate improved the hypercalcemia. Patients had ALL with immunophenotype positive for CD10, CD34, and HLA-DR but negative for CD19 and obtained remission with chemotherapy. These findings suggest that increased osteoclastic bone resorption via stimulation with TNF-alpha and IL-6 may be mechanism causing PTHrP-independent hypercalcemia in some patients with precursor B ALL lacking CD19 expression.

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

“…Moreover, calcitriol-mediated hypercalcemia, the most frequent cause of hypercalcemia in lymphoma, 4 was unlikely in these four patients. Of note, two patients (Cases 19 and 21) had B-precursor ALL with negative-or low-level expression of CD19 and their serum levels of tumor necrosis factor-a and interleukin-6, which are known to promote osteoclastic bone resorption and involve in hypercalcemia in malignancies, 28,29 were elevated at the onset of hypercalcemia, 30 representing an independent subgroup of ALL with PTHrP-independent hypercalcemia.…”

Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κ-B

“…[94][95][96] " Unknown Gain Gain Chronic inflammation 30 " " " Loss Gain Interleukin 1 [31][32][33] " " " Loss Gain Tumor necrosis factor-a 34 The mechanisms for malignancy-associated hypercalcemia and metastatic calcification are variable but include: (1) tumor production of PTH or PTH-related peptide, vitamin D, or various cytokines; (2) upregulation of RANKL; (3) down-regulation of OPG; or (4) a combination of up-regulated RANKL and downregulated OPG. [97][98][99][100][101][102][103][104][105] Like other diseases that are associated with extraosseous mineral deposition, these cancers may be associated with simultaneous osseous mineral loss.…”

Level of Macronutrients and Microelements of Blood Plasma in Different Forms of Pulmonary Tuberculosis

“…There are known humoral compounds promoting the development of hypercalcemia: prostaglandins, transforming growth factors, a number of cytokines (IL-1, IL-4, IL-6, TNF-alpha and TNF-β), which function due to activation of osteoclasts [5]. In the analysis of 23,500 proteins of human proteome, it was found that the functions of 2145 proteins depend to some extent on the level of calcium in the body (for example, the levels of protein expression change), and 625 of the 2145 proteins directly bind the Ca 2+ ion as a cofactor.…”