PubMed · 9048073
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M Kurachi, H Shima, F Ikoma. 1996. [Obstructive uropathy].. https://pubmed.ncbi.nlm.nih.gov/9048073/
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In a previous study of acute leukemia, we have shown that WT1 gene mutations occur in both myeloid and biphenotypic subtypes, where they are associated with refractoriness to standard induction chemotherapy. We have now extended this study to a total of 67 cases (34 acute myeloid leukemia [AML], 23 acute lymphoblastic leukemia [ALL], 10 acute undifferentiated leukemia [AUL]/biphenotypic) and find that WT1 mutations occur in 14% of AML and 20% of biphenotypic leukemia, but are rare in ALL (one case). In contrast to the findings in Wilms' tumor, where mutations in the WT1 gene usually behave according to Knudson's two hit model for tumor suppressor genes, seven of eight leukemia-associated WT1 mutations are heterozygous, implying a dominant or dominant-negative mode of action in hematopoietic cells. In AML, the presence of a WT1 mutation is associated with failure to achieve complete remission and a lower survival rate. These data (1) confirm that WT1 mutations underlie a similar proportion of cases of AML to that seen in Wilms' tumors and (2) show for the first time that WT1 mutations can contribute to leukemogenesis of lymphoid as well as myeloid origin, suggesting that its normal role in hematopoiesis lies at a very early progenitor stage. The relationship of WT1 mutation to chemoresistance merits further investigation.
Transfusion-related acute lung injury (TRALI) is a serious complication of hemotherapy. During blood storage, lipids are generated and released into the plasma. In this study, the role of these lipids in TRALI was investigated using an isolated, perfused rat lung model. Rats were pretreated with endotoxin (LPS) or saline in vivo and the lungs were isolated, ventilated, and perfused with saline, or (a) 5% (vol/ vol) fresh human plasma, (b) plasma from stored blood from the day of isolation (D.0) or from the day of outdate (D.42), (c) lipid extracts from D.42 plasma, or (d) purified lysophosphatidylcholines. Lungs from saline or LPS-pretreated rats perfused with fresh (D.0) plasma showed no pulmonary damage as compared with saline perfused controls. LPS pretreatment/D.42 plasma perfusion caused acute lung injury (ALI) manifested by dramatic changes in both pulmonary artery pressure and edema. Incubation of LPS pre-tx rats with mibefradil, a Ca2+ channel blocker, or WEB 2170, a platelet-activating factor (PAF) receptor antagonist, inhibited ALI caused by D.42 plasma. Lung histology showed neutrophil sequestration without ALI with LPS pretreatment/saline or D.0 plasma perfusion, but ALI with LPS pretreatment/D.42 plasma perfusion, and inhibition of D.42 plasma induced ALI with WEB 2170 or mibefradil. A significant increase in leukotriene E4 was present in LPS-pretreated/D.42 plasma-perfused lungs that was inhibited by WEB 2170. Lastly, significant pulmonary edema was produced when lipid extracts of D.42 plasma or lysophosphatidylcholines were perfused into LPS-pretreated lungs. Lipids caused ALI without vasoconstriction, except at the highest dose employed. In conclusion, both plasma and lipids from stored blood produced pulmonary damage in a model of acute lung injury. TRALI, like the adult respiratory distress syndrome, may be the result of two insults: one derived from stored blood and the other from the clinical condition of the patient.
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