Acute Monocytic Leukemia in an Irradiated Beagle

Tolle, D.V.; Seed, T. M.; Fritz, T.E.; Lombard, Louise S.; Poole, C.M.; Norris, William P.

doi:10.1177/030098587901600210

Cited by 18 publications

(2 citation statements)

References 14 publications

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“…Our aim was to establish a reproducible and clinically relevant model of BM dysfunction that resembled secondary (that is, resulting from therapy) MDS. It has been known for several years, that dogs chronically exposed to low daily doses of whole-body γ-radiation are prone to develop hematologic changes consistent with a myeloproliferative disorder [30], [31]. In our 3-cycle irradiation model (3x irradiation), 40–50% of WT mice presented low WBC, anemia and thrombocytopenia, and elevated MCH-Hemoglobin per RBC (indicative of macrocytic anemia).…”

Section: Discussionmentioning

confidence: 94%

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

et al. 2010

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BackgroundSecondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an increased risk of developing fatal acute leukemias. In the present study we asked whether TNF-α, known to regulate cell apoptosis, could modulate the onset of secondary MDS.Principal FindingsWe show that TNF-α is induced by irradiation and regulates BM cells apoptosis in vitro and in vivo. In contrast to irradiated wild type (WT) mice, TNF-α deficient (TNF-α KO) mice or WT mice treated with a TNF-α-neutralizing antibody were partially protected from the apoptotic effects of irradiation. Next we established a 3-cycle irradiation protocol, in which mice were sub-lethally irradiated once monthly over a 3 month period. In this model, irradiated WT mice presented loss of microsatellite markers on BM cells, low white blood cell (WBC) counts, reduced megakaryocyte (MK) and platelet levels (thrombocytopenia) and macrocytic anemia, phenoypes that suggest the irradiation protocol resulted in BM dysfunction with clinical features of MDS. In contrast, TNF-α KO mice were protected from the irradiation effects: BM cell apoptosis following irradiation was significantly reduced, concomitant with sustained BM MK numbers and absence of other cytopenias. Moreover, irradiated WT mice with long term (≥5 months) BM dysfunction had increased BM angiogenesis, MMPs and VEGF and NFkB p65, suggestive of disease progression.ConclusionTaken together, our data shows that TNF-α induction following irradiation modulates BM cell apoptosis and is a crucial event in BM dysfunction, secondary MDS onset and progression.

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Section: Discussionmentioning

confidence: 94%

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

et al. 2010

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“…Twenty-seven dogs with nonlymphocytic leukemia that have been observed at this laboratory at continuous exposure rates of either 2.5,5,10, or 17 roentgens/22-hour day [3,12,14], included myelogenous leukemia (18 dogs) [2,9,12,14], monocytic, and myelomonocytic leukemia (4 dogs) (12,13], and erythroleukemia (5 dogs) [9,II,12]. In all, there was a welldefined preleukemic phase, but circulating micromegakaryocytes and megakaryoblasts were observed only in the three dogs described here.…”

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confidence: 99%

Circulating Micromegakaryocytes Preceding Leukemia in Three Dogs Exposed to 2.5 R/day Gamma Radiation

Tolle¹,

Cullen²,

Seed³

et al. 1983

Vet Pathol

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The presence of micromegakaryocytes in the blood and bone marrow of humans during the preleukemic phase of acute and chronic myelogenous leukemia and myelomonocytic leukemia is well documented [I, 4, 5, 7, 8, 10, 15), and it has been suggested that it is the single most typical abnormality suggesting a subsequent course towards overt leukemia (6).Three adult purebred beagles that died with myelogenous leukemia during continuous whole-body exposure to 2.5 roentgens/22-hour day of 6OCO gamma irradiation had micromegakaryocytes and megakaryoblasts in the peripheral blood three to ten weeks before leukemic myeloblasts were observed in buffy coat preparations.The cells of interest were 6 to 30 JLm in diameter, mono-, or binucleated, with round or oval nuclei, indistinct nucleoli, and they had a high nuclear/cytoplasmic ratio ( fig. I). Many cells had cytoplasmic blebs ( fig. 2). Cytochemical characterization revealed strong positive staining for both acetylcholinesterase, and a-naphthyl acetate esterase, as well as abundant glycogen with the periodic acid-Schiff stain. The cells were negative with Sudan black, and no detectable myeloperoxidase or naphthol AS-D chloroacetate esterase activity was seen.Other hematologic abnormalities observed during this preleukemic period included progressive refractory anemia, occasional nucleated red blood cells, anisopoikilocytosis, monocytosis, giant platelets, and a left shift to metamyelocytes. Over the same period, bone marrow preparations from iliac crest aspirates and rib biopsies revealed granulocytic hyperplasia with a moderate left shift but without an excess of myeloblasts. There was also erythroid depletion, and increased numbers of mono-, bi-, and multinucleated megakaryocytes ( fig. 3).Ultrastructural characterization clearly indicated the cells to be micromegakaryocytes and megakaryoblasts. Even in the most immature cells, the cytoplasm contained both dense serotonin granules and the characteristic a (bull's-eye) granules, indicating their megakaryocytic lineage (fig. 4). Although the majority of micromegakaryocytes showed dysgenesis of the demarcation membrane system, the cytoplasm did contain smooth, membranous vesicular sacs of a rudimentary demarcation membrane system ( fig. 4) and in a few cells there were flattened, laminar cisternae of the demarcation membrane system with peripheral formation of dystrophic (i.e., agranular, giant) platelets.Terminally, the dogs were severely anemic (0.94, 1.10, and 1.70 X 10 6 red blood cells/ul), and thrombocytopenic (5.0, 7.5, and 90.0 X 10 3/JLI). Total leukocyte counts were 11.5, 14.8, and 57.1 X 10 3 / JLI, respectively. The terminal peripheral blood differential leukocyte count showed a marked left shift (17% myeloblasts) in only one dog. However, bone marrow imprints obtained at necropsy from sternum, rib, and femur showed, in all dogs, a granulocytic hyperplasia with maturation defects and myeloblast counts of 21.0, 11.0, and 35.5% of the total granulocytic series. In all dogs there was a paucity of erythroid elements a...

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Acute Myeloid Leukemia

Stokol¹

2022

Schalm's Veterinary Hematology

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Acute Monocytic Leukemia in an Irradiated Beagle

Cited by 18 publications

References 14 publications

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

Circulating Micromegakaryocytes Preceding Leukemia in Three Dogs Exposed to 2.5 R/day Gamma Radiation

Acute Myeloid Leukemia

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