Tomoya Maeda

Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

PURPOSE To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome. MATERIALS AND METHODS Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined. RESULTS Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase. CONCLUSION The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

A Novel Gene, ANKRD28 on 3p25, Is Fused with NUP98 on 11p15 in a Cryptic 3-Way Translocation of t(3;5;11)(p25;q35;p15) in an Adult Patient with Myelodysplastic Syndrome/Acute Myelogenous Leukemia

We identified a novel gene fusion of ANKRD28 (ankyrin repeat domain 28) on 3p25 to NUP98 on 11p15 in a patient with adult myelodysplastic syndrome/acute myelogenous leukemia. A partially cryptic 3-way translocation, t(3;5;11)(p25;q35;p15), that had initially been supposed to be t(3;5)(p25;q35) was revealed by precise breakpoint mapping via fluorescence in situ hybridization analysis with bacterial artificial chromosome clones. This translocation produces the expression of 2 in-frame fusion transcripts, the novel ANKRD28-NUP98 and NUP98-NSD1, and 1 out-of-frame NSD1-ANKRD28 transcript. Transient overexpression of ANKRD28-NUP98 in NIH/3T3 cells, but not the C-terminal deletion mutant of ANKRD28 (?C-ANKRD28), caused significantly increased focus formation compared with mock-transfectant controls. ANKRD28-NUP98 was localized in the nucleolus and cytoplasm, whereas ANKRD28 and ?C-ANKRD28 were found exclusively in the cytoplasm. Alteration of the subcellular localization of ANKRD28 might have contributed to the leukemogenesis in this case. This report is the first of ANKRD28 as an NUP98 fusion partner, and this case implies that this fusion may be responsible for hematologic malignancies.

Regulation of Calcitonin Receptor by Glucocorticoid in Human Osteoclast-Like Cells Prepared in Vitro Using Receptor Activator of Nuclear Factor-κB Ligand and Macrophage Colony-Stimulating Factor1

Using mouse osteoclast-like cells (OCs), we have shown that treatment with glucocorticoids (GCs) resulted in an increase in calcitonin (CT) binding by enhancing CT receptor (CTR) gene transcription. Additionally, treatment with GCs demonstrated increased sensitivity to CT. There is, however, scant information on the effects of GC or CTR regulation by GCs in human osteoclasts. In this study we examined CTR regulation by GCs and the effects of GCs and CT together in human OCs. OCs were prepared by treatment of peripheral blood mononuclear cells in vitro with soluble receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Treatment of mature OCs with dexamethasone (Dex) resulted in a dose- and time-dependent increase in [125I]salmon CT (sCT) binding capacity. Treatment with Dex enhanced CTR messenger RNA (mRNA) expression, suggesting that CTR up-regulation is at least partly due to an increase in de novo CTR synthesis. Triamcinolone and prednisolone reproduced the Dex effect ...

Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR–ABL-positive ALL

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49–76) and 58% (95% CI, 43–70), respectively. Prognostic factor analysis revealed that the major BCR–ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49–9.08); P=0.005 and HR, 6.25 (95% CI, 1.88–20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21–8.50); P=0.019 and HR, 6.92 (95% CI, 2.09–22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR–ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted.

CD56 expression is an independent prognostic factor for relapse in acute myeloid leukemia with t(8;21)

We investigated the significance of surface antigen expression for prognosis by focusing on a specific subtype, AML with t(8;21). The investigation included 144 patients with AML with t(8;21) in the JALSG AML97 study. AML with t(8;21) expressed CD19 (36%), CD34 (96%), and CD56 (65%) more frequently than did other subtypes of AML. CD19 expression had a significant favorable effect on CR (95.7% vs. 83.8%; P=0.049). Univariate analysis showed that increased white blood cell (WBC) counts (WBC ≥ 20 × 10(9)/L), CD19 negativity, and CD56 positivity were critical adverse factors for relapse after CR; multivariate analysis revealed that WBC count and CD56 expression were independent adverse risk factors (HR 2.18; P=0.045, HR 2.30; P=0.011, respectively). We concluded that CD56 expression has a possible role in risk stratification for patients with AML with t(8;21).

The demarcation between younger and older acute myeloid leukemia patients: A pooled analysis of 3 prospective studies

Contemporary treatment protocols for adult acute myeloid leukemia (AML) are age‐specific, and older patients are generally treated less intensively than younger patients. However, it remains uncertain whether older but fit patients with AML really need to have their treatment attenuated.

Normal karyotype acute myeloid leukemia with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype is a clinically distinct entity with a favorable outcome

Recently, the presence of CEBPA mutation was identified as an important prognostic factor for normal karyotype (NK) acute myeloid leukemia (AML). Because AML with CEBPA mutation is closely associated with CD7, CD15, CD34, and HLA-DR expression, we investigated the prognostic implications of CD7+ CD15+ CD34+ HLA-DR + immunophenotype in NK-AML. We analyzed the immunophenotype of 329 patients with NK-AML from the Japan Adult Leukemia Study Group (JALSG) AML97 population. NK-AML with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype was classified as the CEBPA type, and NK-AML that did not meet this criterion was considered as the non-CEBPA type. The influence of the CEBPA status on event-free survival (EFS) and overall survival (OS) was assessed using log-rank test and a multivariate Cox proportional hazard regression model. Furthermore, the surface antigen expression profile in AML according to the CEBPA mutation status (monoallelic or biallelic) was also investigated. Of the 329 NK-AML patients that were studied, 39 and 243 were classified as having CEBPA and non-CEBPA type NK-AML, respectively. Patients with CEBPA type NK-AML had significantly better EFS and OS than those with non-CEBPA type NK-AML. Multivariate analysis showed that the CEBPA type and white blood cell (WBC) counts of >20 × 109/L were independent prognostic factors for EFS and OS. Moreover, NK-AML with the biallelic CEBPA mutation was more closely associated with CD34 positivity than that with the monoallelic CEBPA mutation. NK-AML with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype is a clinically discrete entity, and this may have a possible role in risk stratification.

Diagnostic performance of procalcitonin, presepsin, and C-reactive protein in patients with hematological malignancies

Infections represent a major complication of hematological malignancies. C‐reactive protein (CRP) and procalcitonin (PCT) have been used as diagnostic biomarkers of infections, but do not produce definitive findings. Recently, a new biomarker, presepsin, has been used as a diagnostic tool for detecting infections in the fields of emergency and neonatal medicine. However, the usefulness of presepsin for identifying infections in patients with hematological malignancies, including those who develop febrile neutropenia, remains unclear.

Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission.

While unrelated bone marrow transplantation (UBMT) has been widely used as alternative donor transplantation, the use of umbilical cord blood transplantation (UCBT) is increasing recently.

Phase II study of imatinib‐based chemotherapy for newly diagnosed BCR‐ABL‐positive acute lymphoblastic leukemia

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib‐combined chemotherapy for newly diagnosed BCR‐ABL‐positive ALL in adults. Sixty‐eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients >55 years of age. Sixty‐five patients achieved CR (95.6%). The estimated 2‐year event‐free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo‐SCT) at initial CR was performed in 43 patients. Thirty‐five of 39 patients <55 years and 8 of 26 patients >55 years underwent allo‐SCT at first CR. The 3‐year OS in patients <55 years receiving allo‐SCT at first CR, patients >55 years receiving allo‐SCT at first CR, patients <55 years not receiving allo‐SCT at first CR, and patients >55 years not receiving allo‐SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three‐year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib‐based chemotherapy allowing allo‐SCT in a high proportion of patients, particularly those <55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo‐SCT. This trial was registered with the UMIN (000001226).