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Circulating erythroid precursors also had cytoplasmic vacuolation and nuclear irregularity. Nonhemoglobin iron Amrinone revealed by Prussian blue staining (abnormal ring sideroblasts, siderocytes) and positive PAS staining (periodic acid-Schiff) suggested features of erythroleukemia. Anemia was characteristic, with the shift toward immature forms signaling an ineffectual regenerative response consistent with lethargy and rapid breathing in end-stage animals. We conclude that deleting Xist in the blood compartment results in multilineage defects, with features characteristic of myelofibrosis, myeloproliferation, and myelodysplasia. Myelofibrosis with myelodysplasia and myeloproliferation indicates a hematological cancer termed myeloproliferative neoplasm. Although the animal presentations varied, general trends were evident and were indistinguishable between Xist��/+ and Xist��/Xist�� mice. The possibility of cancer is supported by several coexisting conditions. Primary manifestations related to two types of leukemia, chronic myelomonocytic leukemia (CMML) and erythroleukemia. CMML features included persistent monocytosis, neutrophilia, pseudo-Pelger-Huet cells (0.5%�C15.0% of circulating WBC), leukocytosis of up to 70,000 WBC/��l ( Figures 3A and 3B), and increased numbers of circulating promonocytes (SCH772984 nmr and 23-2-1 [Xist��/+, 9.6?months]), leukocytosis occurred together with splenomegaly and general lymphadenopathy ( Figure?4A). Large germinal centers showed increased numbers of B cells, disorganized T?cells, histiocytes, and mitotic rates ( Figure?4B). A coexisting erythroleukemia-like syndrome was supported by erythrodysplasia, anemia, and expanded circulating erythroid precursors with positive cytoplasmic PAS and Prussian-Blue staining (e.g., 24-1-4, Xist��/+, 11.9?months; 4-2-3, Xist��/Xist��, 12?months) ( Figures 3A and 3B). Mutant animals also demonstrated a histiocytic sarcoma (HS, also called malignant histiocytosis), a rapidly fatal cancer of unknown but presumed hematologic origin. The HS was female specific (Figure?4C) and characterized by atypical spindloid cells, multinucleated giant cells, marked hemophagocytosis, and?a selleck chemical high mitotic rate (Figure?4D; see inset). Approximately 20% of animals showed widespread HS in bone marrow, pancreas, lung, liver, kidney, and/or lymph nodes (Figure?4D). Local invasion led to spinal compression and limb paralysis (animal 4-2-1, Xist��/Xist��, 9.4?months); renal failure resulted from kidney infiltration. Immunohistochemistry demonstrated a histiocytic but nonLangerhans origin, confirming the diagnosis of metastatic HS ( Figures 4E and 4F: Mac2+, F4/80+, S100?, MPO?, B220?, and CD3?).