ALBERT

Description: Human neutrophil elastase (NE), a 29-Kd potent serine protease stored in azurophilic granules of mature neutrophils, is coded for by the NE gene, a single copy gene with 5 exons spanning a 6-kb segment of chromosome 11 at q14. With the knowledge that the NE gene expression is limited to early myeloid cell differentiation, mechanisms modulating expression of the NE gene were evaluated in the HL-60 promyelocytic leukemia cell line, a model of early bone marrow precursor cells. Consistent with the presence of NE messenger RNA (mRNA) transcripts in undifferentiated HL-60 cells, nuclear transcription run-on analyses showed that HL-60 cells actively transcribed the NE gene. However, the transcription rate of the NE gene was relatively low, only 40% of the myeloperoxidase gene, a gene expressed in parallel with NE. When induced toward the mononuclear phagocytic lineage with phorbol 12- myristate 13-acetate (PMA), HL-60 cells exhibited marked suppression of NE gene transcription, declining to 17% of the resting rate within 2 days. Induction toward mononuclear phagocytic lineage differentiation caused no change in NE mRNA transcript half-life (T1/2), but mRNA levels decreased markedly over time, with levels undetectable 1.5 days after PMA stimulation. In contrast, when induced toward the myelocytic lineage with dimethyl sulfoxide, the rate of NE gene transcription increased 1.9-fold within 5 days. Interestingly, the mRNA transcript levels increased 2.5-fold by 5 days despite the fact that induction toward myelocytic lineage differentiation was accompanied by a marked reduction of NE mRNA transcript T1/2. Together, these observations suggest that the NE gene expression during bone marrow differentiation is modulated mainly at the transcriptional level, with some posttranscriptional modulation contributing, particularly during myelocytic lineage differentiation.

Description: Background: Since the incidence of HL in Japan is approximately one-third of that in western countries, there are few studies on validation of international prognostic score (IPS) in Japanese patients (pts) with HL. Patients and Methods: JCOG-LSG conducted 2 multicenter phase II trials for advanced HL, including ABVd (JCOG9305) and ABV followed by involved-field radiotherapy (JCOG9705). Because dacarbazine was highly emetic, and not approved for HL in Japan in those days, the dose of dacarbazine was reduced to a two-thirds (250 mg/m2) of that in original ABVD regimen in ABVd, and in ABV with increased dose of doxorubicin, dacarbazine was not utilized. Among the whole 200 enrolled pts, histopathological specimens from 181 pts were reviewed by 6 hematopathologists and consensus diagnosis of HL was made in 167 (92.3%), according to the WHO classification. Major eligibility criteria of the trials were age between 15 and 69, ECOG performance status of 0 to 3, and clinical stage of II, III or IV in JCOG9305, and IB, IIB, III or IV in JCOG 9705. Results: 5-year survival of the 167 patients was 88.3%. Histopathological distributions of 167 pts with HL were similar with those in western countries; 2 nodular lymphocytic predominance (1.2%), 115 nodular sclerosis (68.9%), 3 lymphocyte-rich (1.8%), 34 mixed cellularity (20.1%), 7 lymphocyte depletion (4.2%), and 6 unclassified (3.6%). IPS was poorly fitted for the overall survival (OS), mainly because of too good prognosis of patients with IPS-grade 6. Seven unfavorable prognostic factors for OS identified by the univariate analysis were male sex, high β2 microglobulin, B symptoms, high LDH, high alkaline-phosphatase, clinical stage of III or IV, and histopathological subtype (mixed cellularity or lymphocyte depletion). Excluding β2 microglobulin from analysis because of only 105 available data, male sex [HR 3.30 (95%CI: 1.15–9.52, p=0.027) ] and high LDH [HR 2.41 (95%CI: 1.07–5.43, p=0.034)] were significant independent risk factors in a multivariate analysis. Conclusions: Our study suggests that male sex and high LDH might be important prognostic factors in OS of pts with HL. Simple prognostic model for HL, including sex and LDH, was suggested.

Description: Human neutrophil elastase (NE), a 29-Kd potent serine protease stored in azurophilic granules of mature neutrophils, is coded for by the NE gene, a single copy gene with 5 exons spanning a 6-kb segment of chromosome 11 at q14. With the knowledge that the NE gene expression is limited to early myeloid cell differentiation, mechanisms modulating expression of the NE gene were evaluated in the HL-60 promyelocytic leukemia cell line, a model of early bone marrow precursor cells. Consistent with the presence of NE messenger RNA (mRNA) transcripts in undifferentiated HL-60 cells, nuclear transcription run-on analyses showed that HL-60 cells actively transcribed the NE gene. However, the transcription rate of the NE gene was relatively low, only 40% of the myeloperoxidase gene, a gene expressed in parallel with NE. When induced toward the mononuclear phagocytic lineage with phorbol 12- myristate 13-acetate (PMA), HL-60 cells exhibited marked suppression of NE gene transcription, declining to 17% of the resting rate within 2 days. Induction toward mononuclear phagocytic lineage differentiation caused no change in NE mRNA transcript half-life (T1/2), but mRNA levels decreased markedly over time, with levels undetectable 1.5 days after PMA stimulation. In contrast, when induced toward the myelocytic lineage with dimethyl sulfoxide, the rate of NE gene transcription increased 1.9-fold within 5 days. Interestingly, the mRNA transcript levels increased 2.5-fold by 5 days despite the fact that induction toward myelocytic lineage differentiation was accompanied by a marked reduction of NE mRNA transcript T1/2. Together, these observations suggest that the NE gene expression during bone marrow differentiation is modulated mainly at the transcriptional level, with some posttranscriptional modulation contributing, particularly during myelocytic lineage differentiation.