Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.

The distinction between multiple myeloma and Waldenström's macroglobulinemia can usually be made on the basis of clinical, histologic, and immunologic findings. However, some patients have features of both diseases. Two patients who had IgM monoclonal gammopathies and plasma cell neoplasia are presented. Both had bone lesions, monoclonal IgMk, and bone marrow infiltration with plasma cells. The presence of plasma cells was verified by electron microscopy. Immunoperoxidase studies in both cases showed positive staining with mu and kappa antisera only, suggesting that these plasma cells were the source of the IgMk protein. Using the criteria of monoclonal IgM, plasma cell neoplasia, and bone lesions, 28 similar cases were found. The analysis of clinical data revealed an increased incidence of lytic bone lesions, decreased IgG and IgA, renal failure, hypercalcemia, and Bence-Jones proteinuria, as are commonly seen in multiple myeloma. It also demonstrated an increased incidence of hyperviscosity symptoms, lymphadenopathy, hepatosplenomegaly, and mucous membrane bleeding, as are often seen in Waldenström's macroglobulinemia. Other common findings were anemia and plasma cell leukemia. These data suggest that, although rare, IgM myeloma should be considered a distinct clinical entity in the spectrum of B-cell malignancies with characteristics of both multiple myeloma and Waldenström's macroglobulinemia.

The acylation step of the α-chymotrypsincatalyzed hydrolysis of N -acetyl-L (or DL)-tryptophan p -nitrophenyl, p -nitrothiophenyl, ethyl, and thiolethyl esters has been studied by the stopped-flow technique at 25°. The acylation rate constant, k 2 , and the enzyme substrate dissociation constant, K s , were directly determined at pH 4, 5, and 8. Steady-state kinetics were studied at pH 7. The k 2 values are nearly identical for oxygen esters and their sulfur counterparts, whereas the K s value of the ethyl ester is larger by an order of magnitude than those of the other three. The results strongly suggest that oxygen and thiol esters of these specific substrates are hydrolyzed via the same pathway, and furthermore that acylation consists of more than one step, the formation and breakdown of a tetrahedral intermediate, the former being rate-determining. Effects of leaving-group hydrophobicity on k 2 and K s are also discussed.