Hereditary hemolytic anemia, a dominantly transmitted disorder, has affected 12 family members spanning three generations. The concentration of adenosine triphosphate in the red cells was about half that of comparably reticulocyte-rich blood. Since adenosine deaminase and adenosine kinase compete for a common substrate, the greatly increased activity of the former may interfere with nucleotide salvage via the latter.
Acute thrombotic and hemorrhagic manifestations of thrombocytosis associated with myeloproliferative disorders may be life threatening. Conventional therapy with radioisotopes and/or cytotoxic drugs may require weeks for effective control of platelet counts. In five patients, plateletpheresis by discontinuous-flow (Haemonetics) or continuous-flow (Aminco Celltrifuge) centrifugation was used as a means of reducing platelet counts acutely. With each procedure, approximately 2–9 X 10(12) platelets were removed, resulting in decrements in platelet counts and relief of symptoms. Plateletpheresis is a useful and safe acute means of controlling platelet counts in myeloproliferative disorders.
We have investigated the molecular basis of the marked elevation in erythrocyte adenosine deaminase (ADA) activity in a kindred with hereditary hemolytic anemia. Red cell ADA-specific activity was verified to be 70-to 100-fold normal levels. Western blots demonstrated a corresponding increase in erythrocyte ADAspecific immunoreactive protein. Analysis of genomic DNA revealed no evidence for amplification or major structural changes in the ADA gene. ADA-specific messenger RNA (mRNA) from proband reticulocytes was comparable in size and amount to mRNA from control reticulocytes. Translation of proband poly A' reticulocyte mRNA in a rabbit reticulocyte lysate system and immunoprecipitation of 3_S-labeled protein products with anti-ADA antibody yielded a band of -42,000 apparent mol wt that was absent in translation products from control reticulocyte mRNAs. These data suggest that the increased ADA activity in red cells in this disorder results from the increased translation of an aberrant ADA mRNA.
Monocytes contain a characteristic, prominent set of membrane-bound nonspecific esterases with a slightly acid isoelectric point. These esterases are also detected at modest levels in some granulocyte preparations. They are not apparent in lymphocytes. Among 18 fresh myeloid leukemias and myeloid leukemia cell lines, those of subtypes M4 (myelomonocytic) and M5 (monocytic) were strongly positive; some of subtypes M1-M3 (granulocytic) were moderately positive. The esterases were not detected among 32 fresh lymphoid leukemias and lymphoid leukemia and lymphoblast cell lines. The membrane-bound monocyte esterases, solubilized by treatment of monocyte preparations with nonionic detergent, were resolved by ion-exchange chromatography. The monocyte species account for 80-95% of the total nonspecific esterase activity of monocytes. The resolved enzymes behave as neutral serine carboxyl esterases and are highly sensitive to inhibition by diisopropylfluorophosphate (DFP) and also by sodium fluoride. Similar analysis of a lymphocyte preparation yielded no detectable monocyte esterases, but yielded numerous other forms which were generally resistant to inhibition by DFP and NaF. These nonspecific esterases are also present at background levels in monocytes. The resolution and characterization of the membrane-bound serine esterases from monocytes demonstrates the basis for the well-known cytochemistry of monocytes. The results are also crucial to the development of an immunologic surface marker test for myeloid cells and the study of monocyte membrane physiology.
A marked tissue-specific increase in erythrocyte adenosine deaminase (ADA) activity is associated with an autosomal dominantly inherited hemolytic anemia. We investigated the molecular basis of ADA overproduction by studying reticulocyte ADA mRNA from affected individuals. Analysis of proband reticulocyte ADA cDNA clones revealed normal sequence. RNase mapping demonstrated that the amount of ADA mRNA in affected reticulocytes was greater than the amount in normal B lymphoblasts, whereas ADA mRNA was undetectable in normal reticulocytes. The 5′- and 3′-untranslated regions of reticulocyte and B-lymphoblast ADA mRNAs from affected individuals were structurally indistinguishable from those of normal B lymphoblasts. Northern blot analysis performed under stringent hybridization and washing conditions confirmed a markedly increased amount of reticulocyte ADA mRNA in affected individuals as compared with controls. We conclude that the RBC-specific overexpression of ADA in this disorder occurs at the mRNA level.
New definitions of response for patients with AML have been suggested, e.g. CRp, marrow CR, hematologic improvement. Although the criteria for these are less demanding than those for CR, some have proposed that their attainment can convert AML to a “chronic disease” associated with long-term survival. To test this hypothesis, we used ECOG and MDA data to assess the effect of the achievement of CR rather than responses < CR following initial Rx on probabilities of survival 3 and 5 years after diagnosis. 2,061 pts treated on 6 ECOG trials 1976–1999 and 1,651 pts given various ara-C-containing regimens at M.D. Anderson 1980–1999 formed our database. We excluded from the survival analyses the 473 pts (11% ECOG,16% MDA)who died within 4 weeks of beginning treatment. CR rates were 62% and 60% for ECOG and MDA pts, respectively. 11% of ECOG and 54% of MDA pts were age ≥ 60. CR rates in these pts were 46% ECOG and 49% MDA. Survival probabilities according to site and response to initial Rx are as follows:
Group Site/Response to Initial Rx Patients Probability Survival at 3 Years (%+/−SE) Probability Survival at 5 Years (%+/− SE) All Pts ECOG/CR 1277 38+/− 1 33+/−1 MDA/CR 996 30+/−1 24+/−1 ECOG/<CR 567 11+/1 9+/−1 MDA/<CR 399 4+/−1 2+/−0 Age ≥ 60 ECOG/CR 106 25+/4 15+/−3 MDA/CR 374 19+/2 12+/−2 ECOG/<CR 62 2+/2 0+/−0 MDA/<CR 221 2+/−1 0+/−0 Age < 60 ECOG/CR 1171 39+/−1 34+/−1 MDA/CR 622 38+/−2 31+/2 ECOG/<CR 505 12+/−1 10+/−1 MDA/<CR 178 6 +/−2 4+/−2
We are assessing whether pts who survived 3 or 5 years despite not achieving CR with initial Rx attained CR with salvage Rx (e.g. allogeneic transplant) or had CRp or marrow CR rather than complete resistance after initial Rx. Nonetheless, our data indicate that in older pts given ara-C-containing regimens, long-term survival is essentially impossible without achievement of CR. Similarly, very few younger pts not achieving CR survive at 3–5 years. Therefore, it appears likely that newer “targeted agents” will have to contribute more than producing responses < CR and must fundamentally change the biology of the disease to improve long-term survival in AML.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.