No abstract

GM-CSF signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity. We observed that GM treatment of RE HSPCs resulted in a unique gene expression profile that resembles primary human cells undergoing myelopoiesis, which was not observed in control HSPCs. Additionally we discovered that GM-CSF signaling attenuates MYC-associated gene signatures in RE HSPCs. In agreement with this, a functional screen of a subset of GM-CSF-responsive genes demonstrated that a MYC inhibitor, MXI1, reduced the leukemic potential of RE HSPCs and t(8;21) AML cells. Furthermore, MYC knockdown and treatment with the BET inhibitor JQ1 reduced the leukemic potential of t(8;21) cell lines. Altogether, we discovered a novel molecular mechanism mediating the GM-CSF-induced reduction in leukemic potential of RE cells, and our findings support MYC inhibition as an effective strategy for reducing the leukemogenicity of t(8;21) AML.

No abstract

The McCune-Albright syndrome is characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction (Albright, Butler, Jampton and Smith 1937). In addition to precocious puberty described in Albright's original patients, other endocrinopathies, including hyperthyroidism, hyperparathyroidism, Cuishing's syndrome, have been reported (Harris 1984), but only six had biochemical evidence of nonsuppressible growth hormone excess (Harris 1984). Our present report demonstrates that acromegaly and hyperprolactinaemia can occur in a patient with McCune-Albright syndrome without any evidence of other endocrine involvement.The patient was a 30-year-old clerk who complained of changes in facial appearance for 15 years and progressive increase in shoe sizes in the past five years. She also noticed mild headache. Menarche occurred at the age of 12 and the menstruation has been regular ever since. Physical examination showed that she was a tall girl, with bilateral maxillary prominence, hypertelorism and macrognathia. The face, hands and feet were broad, with excessive sweating. Secondary sexual characteristics were normal and galactorrhoea was absent. There was no area of hyperpigmentation. The thyroid was not palpable. Visual fields were normal. Endocrine evaluation demonstrated a reduced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to LH-releasing hormone (LH-RH). The basal levels of serum growth hormone and prolactin were 129 mU/l (normal < 10 mU/1) and 1871 mU/1 (normal < 650 mU/1) respectively. Serum oestradiol, throxine, thyroid-stimulating hormone and Cortisol were within normal limits. Serum osmolality was 286 mOsm/kg, while the simultaneous urine osmolality was 852 mOsm/kg. Oral glucose tolerance test (75 g glucose) showed that fasting glucose was elevated (8.4 mmol/1) and glucose peaked at 60 min (14.2 mmol/1) and remained elevated at 120 min (11.6 mmol/1). Simultaneous GH levels showed high basal GH (118 mU/1) which further increased to 132 mU/1 at 90 min when the glucose was 12.2 mmol/1. Skeletal roentgenograms showed involvement of the skull, mandible, pelvis, transverse process of L4 and right tibia by fibrous dysplasia (Fig. 1). CT scan of pituitary gland showed that the right side of the pituitary gland was enlarged, with bulging upper surface and displacement of the pituitary stalk to the left. There was marked extension of the mass inferiorly and posteriorly. The diagnosis of acromegaly with hyperprolactinemia was made. Transphenoidal surgery was considered hazardous in view of the structural abnormalities and vascularity of the facial and sphenoidal bones. She was treated with bromocriptine and radiotherapy.The endocrine and systemic manifestations of the McCune-Albright syndrome are interesting and puzzling. The syndrome was first reported by McCune and Bruck and shortly thereafter by Albright et al. (1937). Endocrine manifestations that have been associated with this syndrome include precocious puberty and hyperthyFig.