三村 尚也

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.

Myeloid/lymphoid neoplasms with PDGFRB rearrangement are a distinct type of myeloid neoplasms that occur in association with rearrangement of PDGFRB at 5q32. The hematological features most often show prominent eosinophilia. We herein report a patient with myeloid/lymphoid neoplasms with PDGFRB rearrangement with t (5;10) (q33;q22) who showed atypical chronic myeloid leukemia-like clinical features without eosinophilia and achieved an optimal response to imatinib. A sequence analysis showed a CCDC6-PDGFRB fusion gene with a new break point in the PDGFRB gene. This is the sixth case of myeloid/lymphoid neoplasm with PDGFRB rearrangement harboring a CCDC6-PDGFRB fusion gene, and it has a new breakpoint in the PDGFRB fusion gene.

Mediastinal gray zone lymphoma (MGZL) is a provisional entity with intermediate features between classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma. Outcomes for patients with MGZL are reportedly poorer than those for patients with cHL or primary mediastinal large B-cell lymphoma. Additionally, no standard management guidelines for patients with MGZL are available, primarily due to its recent identification, rarity, and challenges in diagnosis. Although recent several studies have suggested dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and rituximab) may improve outcomes in patients with MGZL, numerous patients still suffer from relapsed/refractory MGZL, and the optimal management for such patients remains uncertain. Here, we report the first case of successful treatment of refractory MGZL by tandem high-dose chemotherapy supported by autologous stem cell transplantations (auto-SCTs) and consolidative radiotherapy (RT). To date, the patient remains in CR 33 months after the completion of RT, with no significant complications. This case suggests that tandem auto-SCTs may be a promising therapeutic option for relapsed/refractory MGZL.

Thrombopoietin-receptor agonists have been recently introduced for a second-line treatment of immune thrombocytopenia (ITP). Splenectomy has tended to be avoided because of its complications, but the response rate of splenectomy is 60–80% and it has still been considered for steroid-refractory ITP. We performed partial splenic embolization (PSE) as an alternative to splenectomy. Between 1988 and 2013, 91 patients with steroid-resistant ITP underwent PSE at our hospital, and we retrospectively analyzed the efficacy and long-term outcomes of PSE. The complete response rate (CR, platelets CloseSPigtSPi 100 × 109/L) was 51% (n = 46), and the overall response rate (CR plus response (R), CloseSPigtSPi 30 × 109/L) was 84% (n = 76). One year after PSE, 70% of patients remained CR and R. The group with peak platelet count after PSE ≥ 300 × 109/L (n = 29) exhibited a significantly higher platelet count than the group with platelet count OpenSPiltSPi 300 × 109/L (n = 40) at any time point after PSE. The failure-free survival (FFS) rates at 1, 5, and 10 years were 78, 56, and 52%, respectively. Second PSE was performed in 20 patients who relapsed (n = 14) or had no response to the initial PSE (n = 6), and the overall response was achieved in 63% patients. There were no PSE-related deaths. These results indicate that PSE is a safe and effective alternative therapy to splenectomy for patients with steroid-resistant ITP as it generates long-term, durable responses.

We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ER alpha and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERa, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer.

We report a 34-year-old woman with eating epilepsy induced not only by eating but also seeing foods made of minced meat. In her early 20s of age, she started having simple partial seizures (SPS) as flashback and epigastric discomfort induced by particular foods. When she was 33 years old, she developed SPS, followed by secondarily generalized tonic-clonic seizure (sGTCS) provoked by eating a hot dog, and 6 months later, only seeing the video of dumpling. We performed video electroencephalogram (EEG) monitoring while she was seeing the video of soup dumpling, which most likely caused sGTCS. Ictal EEG showed rhythmic theta activity in the left frontal to mid-temporal area, followed by generalized seizure pattern. In this patient, seizures were provoked not only by eating particular foods but also by seeing these. This suggests a form of epilepsy involving visual stimuli.

同種造血幹細胞移植は、高度な倫理性と専門性を有した多職種が関与する集学的チーム医療であり、造血細胞移植コーディネーター(HCTC)は、ドナーと移植患者双方の安全と支援に寄与する役割を担う。当院では、2014年に輸血・細胞療法部医師とHCTCにより、患者と独立した立場でドナーの安全性確保を目的としたドナー外来を開設した。今回、開設後1年間に当外来を受診した血縁ドナー候補者30例を対象にドナー外来の有用性と意義について解析した。30例のうち14例が他院で既にHLA検査を施行されていた。医師による造血幹細胞提供に関する包括的な説明の後、HCTCは、チェックシートに従い健康状態と提供意思を確認し、担当医と第3者の医師を含めた3者の協議によりドナー適格性を判定した。30例中5例(うち3例は受診前HLA検査施行例)が不適格と判定された。他院でHLA検査を施行した14例中2例は、幹細胞提供に関する十分な理解が得られていなかった。また3例は問診にて不適格と判定された。ドナー候補者には、患者とは独立した立場の医師及びHCTCによりHLA検査施行前に十分なインフォームドコンセントを得ることと問診による適格性判定が必要であり、HCTCと輸血・細胞療法部医師によるドナー外来はドナーの安全性と倫理性の高いコーディネート体制を確立する上で有用であると考えられる。(著者抄録)

Purpose: EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer. Experimental Design: In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in multiple myeloma. The efficacy of the combination therapy was validated in prostate cancer cell lines. Results: Proteasome inhibitors repressed EZH2 transcription via abrogation of the RB-E2F pathway, thereby sensitizing EZH2-dependent multiple myeloma cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic antimyeloma activity in vitro. Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo. Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1. Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells. Conclusions: Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers. (C) 2017 AACR.

形質細胞の悪性腫瘍である多発性骨髄腫は未だ治癒困難な血液がんである。骨髄腫細胞は多様な遺伝子変異やシグナル伝達経路を持ち,また骨髄微小環境に守られて薬剤耐性を獲得している。我々は今までに,骨髄腫細胞生存の鍵である小胞体ストレス応答を標的にしたIRE1α-XBP1阻害剤,重要なシグナル伝達経路を標的とした新規選択的Akt阻害剤,エピジェネティック機構を標的としたヒストンメチル化酵素EZH2とEZH1の共阻害剤について,骨髄腫の前臨床での治療効果とそのメカニズムを明らかにし,特にこれらの新規薬剤とプロテアソーム阻害剤による併用療法が有望であることを示してきた。本総説ではこれらの知見を元に,多発性骨髄腫の治癒に向けた新規分子標的療法について概説したい。(著者抄録)

症例は46歳の男性。1ヵ月前より全身倦怠感および黄疸が出現したため近医を受診した。血液検査にて末梢血の芽球出現を伴う汎血球減少と黄疸を認めたため、精査・加療目的で当院を紹介受診した。骨髄検査では芽球様細胞(90.2%)を認め、遺伝子検査にてPML-RARA融合遺伝子が検出されたことから、急性前骨髄球性白血病(APL)と診断された。また腹部ダイナミックCTでは、胆管浸潤を伴った多発性肝細胞癌(HCC)が認められた。一過性の胆道出血を認めたものの胆管炎の合併はなかったため、APLに対する治療を優先し、全トランス型レチノイン酸(ATRA)による寛解導入療法を開始した。入院後1ヵ月の時点でAPLの血液学的完全寛解を確認したため、HCCに対して肝動脈化学塞栓術(TACE)を施行した。その後亜ヒ酸を用いた地固め療法およびATRAによる維持療法を行い、APLは寛解が維持された。一方で、TACEによるHCCの制御は困難であり、経過中に多発性肺転移を認めた。ソラフェニブによる全身化学療法を開始したが、投与開始後1ヵ月の時点でHCC破裂を来たし、当院受診後11ヵ月で死亡した。(著者抄録)

p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of proapoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-typep53 MM. 1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axisdependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM. (Blood. 2017;129(10):1308-1319)

Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor beta 1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown. Combined analyses of chromatin immunoprecipitation followed by sequencing and RNA-sequencing led to successful identification of 96 candidate epigenetic targets of G9a. Pharmacological inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. Intraperitoneal administration of BIX-01294 suppressed the growth of xenograft tumors generated by implantation of HCC cells in non-obese diabetic/severe combined immunodeficient mice. Immunohistochemical analyses revealed high levels of G9a and H3K9me2 in 36 (66.7%) and 35 (64.8%) primary HCC tissues, respectively. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues. In contrast, in non-tumor tissues, G9a and H3K9me2 were only observed in biliary epithelial cells and periportal hepatocytes. In conclusion, G9a inhibition impairs anchorage-dependent and -independent cell growth, but not EMT in HCC cells. Our data indicate that pharmacological interference of G9a might be a novel epigenetic approach for the treatment of HCC.

Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony-stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers >= 2.0 x 10(6) CD34(+) cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P=.71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection. (C) 2017 American Society for Blood and Marrow Transplantation.

症例は72歳男性。C型肝炎を背景に発症した門脈本幹腫瘍塞栓を伴う多発性肝細胞癌(HCC)に対して、大腿動脈アプローチでリザーバーシステムを留置した後に同日より肝動注療法(low dose FP療法)を開始し、一旦退院となった。しかし、治療開始後16日目の外来受診時に血小板数が0.3×10^4/μLと著明な減少を認めたために緊急入院となった。赤血球数、白血球数は正常であり、骨髄穿刺所見もほぼ正常であった。播種性血管内凝固症候群、特発性血小板減少性紫斑病などとの鑑別が問題となったが、ヘパリン起因性血小板減少症(HIT)抗体が陽性であったために、HITを強く疑った。ヘパリンの投与中止およびアルガトロバン20mg/日の投与を開始したが、血小板数の回復がほとんど見られず、ヘパリン化親水性カテーテルも抜去した。その後緩やかに血小板数の上昇を認めたが、HCCの病勢進行を認め、動注療法開始後39日目に永眠された。(著者抄録)

Infections of the central nervous system (CNS) with varicella zoster virus (VZV) is a rare occurrence after allogeneic hematopoietic stem cell transplantation. We herein report a case of VZV meningitis, radiculitis and myelitis that developed 8 months after cord blood transplantation, shortly after the cessation of cyclosporine and low-dose acyclovir. Although treatment with acyclovir did not achieve a satisfactory response, the patient was successfully treated with foscamet. Our report indicates that VZV infection should be considered in allo-hematopoietic stem cell transplantation (HSCT) patients with CNS symptoms and that foscarnet may be effective for the treatment of acyclovir-resistant VZV infections of the CNS. The development of optimal prophylactic strategies and vaccination schedules may eradicate post-transplant VZV disease.

Background: LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL Results: Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean SD: 21.2 +/- 27.6 vs. 8.8 +/- 1.8 ng/ml, P < 0.0001), and significantly reduced at remission (mean +/- SD: 17.4 +/- 16.4 vs. 10.9 +/- 4.5 ng/ml, P = 0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (<= 18.1 ng/ml vs. >18.1 ng/ml; 2-y OS: 89.0% vs. 56.4%, P < 0.0001; 2-y PFS: 85.8% vs. 56.9%, P < 0.0001). Conclusions: Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL. (C) 2016 Elsevier B.V. All rights reserved.

Expression of the tumor suppressor gene NR4A3 is silenced in the blasts of acute myeloid leukemia (AML), irrespective of the karyotype. Although the transcriptional reactivation of NR4A3 is considered to have a broad-spectrum anti-leukemic effect, the therapeutic modalities targeting this gene have been hindered by our minimal understanding of the transcriptional mechanisms regulating its expression, particularly in human AML. Here we show the role of intragenic DNA hypermethylation in reducing the expression of NR4A3 in AML. Bisulfite sequencing analysis revealed that CpG sites at the intragenic region encompassing exon 3 of NR4A3, but not the promoter region, are hypermethylated in AML cell lines and primary AML cells. A DNA methyltransferase inhibitor restored the expression of NR4A3 following a reduction in DNA methylation levels at intragenic CpG sites. The in silico data revealed an enrichment of H3K4me1 and H2A.Z at exon 3 of NR4A3 in human non-malignant cells but that was excluded specifically in leukemia cells with CpG hypermethylation. This suggests that exon 3 represents a functional regulatory element involved in the transcriptional regulation of NR4A3. Our findings improve the current understanding of the mechanism underlying NR4A3 silencing and facilitate the development of NR4A3-targeted therapy. (C) 2016 Elsevier Ltd. All rights reserved.

Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.

症例は34歳男性。汎血球減少を主訴に来院し,急性前骨髄球性白血病(APL)と診断してall-trans retinoic acid(ATRA)を開始した。第25病日に発熱,呼吸困難,肺浸潤影を認め,分化症候群(DS)と診断。ATRA投与を中止し,ステロイド投与にて改善した。第29病日にATRAを半量より再開後,口内炎・咽頭痛の増悪を認めたため第37病日にATRAを中止し,酸素化の悪化を認め第42病日にステロイドを増量した。第48病日に突然右下腹部痛を訴え,回盲部の消化管穿孔と診断され緊急回盲部切除術を行った所,回盲部に多発潰瘍と穿孔を認めた。APLは分子学的寛解が得られ,亜ヒ酸にて地固め療法を行い,完全寛解を維持している。本症例ではATRAまたはATRAによるDSが重篤な口内炎や消化管穿孔の原因の一つと考えられた。また,HLA-B51陽性であり,DSに伴う高サイトカイン血症がベーチェット病と類似した病態を誘発した可能性も示唆される。(著者抄録)

症例は34歳男性。汎血球減少を主訴に来院し,急性前骨髄球性白血病(APL)と診断してall-trans retinoic acid(ATRA)を開始した。第25病日に発熱,呼吸困難,肺浸潤影を認め,分化症候群(DS)と診断。ATRA投与を中止し,ステロイド投与にて改善した。第29病日にATRAを半量より再開後,口内炎・咽頭痛の増悪を認めたため第37病日にATRAを中止し,酸素化の悪化を認め第42病日にステロイドを増量した。第48病日に突然右下腹部痛を訴え,回盲部の消化管穿孔と診断され緊急回盲部切除術を行った所,回盲部に多発潰瘍と穿孔を認めた。APLは分子学的寛解が得られ,亜ヒ酸にて地固め療法を行い,完全寛解を維持している。本症例ではATRAまたはATRAによるDSが重篤な口内炎や消化管穿孔の原因の一つと考えられた。また,HLA-B51陽性であり,DSに伴う高サイトカイン血症がベーチェット病と類似した病態を誘発した可能性も示唆される。(著者抄録)

症例は23歳女性。持続する発熱,息切れを主訴に受診。CTにて著明な心嚢水貯留,肝脾腫,軽度の頸部・縦隔リンパ節腫脹があり,EBV抗体価異常,血中EBV-DNA高値から,慢性活動性EBウイルス感染症(CAEBV)と診断した。末梢血リンパ球におけるEBV感染細胞はCD4+T細胞であった。Prednisolone,etoposide,cyclosporineによる治療を開始し,熱型,心嚢水貯留は改善したが,血中EBV-DNAの改善を認めなかったため,フルダラビン,メルファランによる前処置後EBV未感染のHLA一致同胞ドナーより同種末梢血幹細胞移植を施行した。皮膚急性移植片対宿主病(grade 2)を発症したが移植後経過は順調であり,移植後98日目に末梢血EBV-DNAは陰性化し,全身状態良好で無病生存中である。CAEBVはT細胞やNK細胞にEBウイルスが持続感染して発症する予後不良な疾患であり,早期に適切な治療を行い,同種造血幹細胞移植を考慮することが必要である。CAEBVは心嚢水貯留を主症状として発症することもあり,注意すべき徴候であると考えられる。(著者抄録)

We describe two cases of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome patients with deteriorated extravascular volume overload without increased levels of vascular endothelial growth factor after the administration of cyclophosphamide + granulocyte colony-stimulating factor for stem cell mobilization. We then measured the serum levels of 27 cytokines from these cases using a multiplex suspension array system. The analysis revealed the changes of cytokine profiles before cyclophosphamide + granulocyte colony-stimulating factor and after the development of capillary leak symptoms in both cases. This may improve our current level of understanding of the pathogenesis of POEMS syndrome not driven by vascular endothelial growth factor. (C) 2015 Elsevier Ltd. All rights reserved.

Adoptive immunotherapies have been developed for antiviral agent-refractory cytomegalovirus (CMV) disease after stem cell transplantation (SCT). However, the application of such strategies is limited, particularly in terms of need for donor cooperation regarding blood sampling and inaccessibility in the setting of cord blood transplantation. Herein, we describe the first successful treatment of antiviral agent-refractory CMV enteritis after allogeneic SCT by the infusion of ex vivo-expanded donor-derived CD4(+) lymphocytes obtained from the recipient's peripheral blood. This article is protected by copyright. All rights reserved.

KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma ( MM) has not been elucidated. Here we identify KDM3A-KLF2-IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

Multiple myeloma (MM) is a plasma-cell malignancy which remains incurable despite the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcomes. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

Acute myeloid leukemia (AML) with mixed lineage leukemia-eleven-nineteen lysine-rich leukemia (MLL-ELL) is a rare subtype of MLL-rearranged AML. The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with this disease remains unknown. In the present study, we retrospectively investigated the efficacy of allo-HSCT in eight adult MLL-ELL-positive AML patients. Although all eight patients achieved first complete remission (CR1), three (37.5 %) patients experienced relapse after induction therapy. Five (62.5 %) patients underwent allo-HSCT during CR1, whereas two (25.0 %) underwent allo-HSCT during disease relapse, and one (12.5 %) during CR2. All three patients who received allo-HSCT beyond CR1 died due to AML progression after allo-HSCT. Of the five patients who received allo-HSCT during CR1, three (60.0 %) remained alive at study conclusion. The overall survival rate at five years was 50.0 %. Intriguingly, clonally expanded non-leukemic cells expressing MLL-ELL during consolidation therapy were found to be eradicated after allo-HSCT during the monitoring of minimal residual disease in one patient; this indicates that allo-HSCT is efficacious for eliminating pre-leukemic cells resistant to chemotherapy. In conclusion, allo-HSCT soon after CR1 represents a promising therapeutic option for adult AML patients with MLL-ELL, although the outcome of allo-HSCT for patients beyond CR1 was dismal.