Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor.

To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872-11877) was composed of the interleukin 5 receptor alpha chain(+) (IL-5Ralpha(+)) and IL-5Ralpha(-) fractions, and the former was the hEoP. The IL-5Ralpha(+)CD34(+)CD38(+)IL-3Ralpha(+)CD45RA(-) hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Ralpha(-) hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an "IL-5Ralpha-negative" criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders.

The consequences of tacrolimus blood concentrations during the four weeks following marrow transplantation from an unrelated donor: a single-center experience.

In our institute, tacrolimus was started at a dose of 0.03 mg/kg/day and adjusted to maintain a blood concentration between 10 and 20 ng/mL combined with short term methotrexate after bone marrow transplantation from an unrelated donor. Dose adjustment was performed strictly, in order to prevent grade II-IV acute graft-versus-host disease (GVHD)while avoiding renal toxicity of tacrolimus. Then, in this study, we retrospectively evaluated the tacrolimus blood concentration during the first 4 weeks after transplantation. The mean tacrolimus concentration of the eligible 52 patients was 17.41+/-4.84(range, 9.5-33.4)ng/mL in the 1st week after transplantation, but declined to 13.7+/- 4.0(range, 8.1-25.6)ng/mL in the 2nd week. The dose of tacrolimus was decreased as follows: 0.022+/-0.005 mg/ kg/day(range 0.011-0.039)in the 1st week, and 0.018+/-0.007 mg/kg/day(range 0.004-0.040)in the 2nd week. The incidence of grade II-IV GVHD was 63.0% and grade III-IV was 13.9%. The individual variations of tacrolimus blood concentration did not affect the incidence of grade II-IV acute GVHD, as far as the concentration being maintained in the range of 14.82+/-4.22 ng/mL during the first 4 weeks after transplantation. In addition, the variations of tacrolimus concentration didn?t associate statistically with renal toxicity.

Myeloid/natural killer cell blast crisis representing an additional translocation, t(3;7)(q26;q21) in Philadelphia-positive chronic myelogenous leukemia.

We encountered a patient in blast crisis (BC) with chronic myelogenous leukemia (CML) who showed immunophenotypic features similar to those previously described in acute myeloid/natural killer (NK) cell precursor leukemia. The blasts were positive for CD7, CD33, CD34, and CD56. Cytogenetic analysis disclosed a Philadelphia chromosome (Ph) and t(3;7)(q26;q21). Molecular analysis did not detect any EVI1/CDK6 chimeric transcript generated by t(3;7)(q26;q21), but did indicate overexpression of EVI1, which occurs frequently in progression to myeloid BC in CML. Three cases of myeloid/NK cell precursor BC in CML have been reported, but this case is the first to present with Ph and EVI1 abnormality. These observations suggested that a myeloid/NK cell precursor might have been involved in the Ph-positive clone and have been a target for blastic transformation of CML, although EVI1 expression is not specific for transformation to BC from myeloid/NK lineage.