bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of STAT5 by IL-1β or the Inhibitor of Janus Kinases Stimulates Dormant Human Leukemia Stem Cells and Sensitizes Them to Anti-Leukemia Agents.
Authors: Ikezoe Takayuki , Jing Yang , Nishioka Chie , Kojima Shinsuke , Takeuchi Asako , Yokoyama Akihito 
Published: October 2019

Abstract
Abstract 1597
Poster Board I-623
Leukemia stem cells (LSCs) are in a quiescent state, which maybe contributes to their drug-resistant character. It is essential to eradicate LSCs to develop curative therapy for leukemia. To verify molecular mechanisms by which LSCs maintain a dormant state, we examined the activity of the major pro-survival signal pathways in LSCs (CD34+/CD38- compartment) and non-LSCs (CD34+/CD38+ compartment) counterparts from patients with acute myelogenous leukemia (AML, n=3) and acute lymphoblastic leukemia (ALL, n=1) by FACS. Interestingly, LSCs compartment expressed a greater amount of the phosphorylated forms of STAT5 (p-STAT5) than non-LSCs counterparts in all patients. Further studies found that levels of interleukin-1b (IL-1b) were significantly down-regulated in LSCs compared with non-LSCs (p<0.05) and normal hematopoietic stem cells (p<0.01), as measured by real-time RT-PCR. Importantly, exposure of LSCs to IL-1b (50 ng/ml) dephosphorylated STAT5 and decreased the population of cells in a dormant state, as assessed by cell cycle analysis. In addition, blockade of JAK2/STAT5 signaling by the specific JAK2 inhibitor AZ960 stimulated cell-cycling in LSCs in conjunction with down-regulation of cyclin-dependent kinase inhibitor p21waf1. As expected, IL-1b and AZ960 sensitized LSCs to cytarabine and the inhibitor of the FLT3 kinase, as assessed by clonogenic assay. Moreover, this study found that LSCs expressed a greater amount of anti-apoptotic protein Bcl-xL than non-LSCs counterparts. Exposure of LSCs to AZ960 potently induced apoptosis in parallel with down-regulation of Bcl-xL, as assessed by induction of the cleaved forms of PARP. Taken together, JAK2/STAT5 signaling may be a promising molecular target to eradicate LSCs in individuals with AML and ALL.

Disclosures
No relevant conflicts of interest to declare.
Baseline Serum Ferritin Predicts Rate of Infection in Patients with Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome.
Authors: Mattiuzzi Gloria , Amin Hesham M. , Kantarjian Hagop , Garcia-Manero Guillermo , Cortes Jorge 
Published: October 2019

Abstract
Abstract 1611
Poster Board I-637
Excess iron adversely affects the phagocytic, chemotactic and bactericidal activities of neutrophils and monocytes; inhibits the activity of natural killer cells and macrophages, and enhances the ability of microbes to grow in various host tissues. Iron overload has also been described to be an important risk factor for the development of mucormycosis. Serum ferritin is a surrogate marker of iron overload. Studies in recipients of bone marrow transplantation showed that elevated pre-transplant serum ferritin levels (as markers of iron overload) were associated with a high incidence of infection-related mortality.

Objective
1) To evaluate iron overload as a predictor of infection in patients with acute myelogenous leukemia (AML) or high risk myelodysplastic syndrome (HR-MDS) undergoing chemotherapy (CHEMO); 2) to compare baseline bone marrow iron stores (BMIS) versus baseline serum ferritin as predictor of infections.

Methods
Patients with AML or HR-MDS who underwent induction or first salvage CHEMO were included in this prospective observational study. BMIS was analyzed at baseline (prior CHEMO) in bone marrow aspirate smears by standard staining techniques. BMIS was evaluated using a light microscope and graded on a scale of 0 to 6, with a score of 1 to 3 considered normal. Serum ferritin levels were measured at baseline. Invasive fungal infections (IFI) were defined as probable or proven according to the EORTC-MSG criteria. Bacterial infections were defined by the presence of fever and positive culture from a sterile site. Ferritin values were considered normal if they fell in the range of 10ng/mL – 291ng/mL.

Results
112 patients were evaluated. Median age was 69 years (23-84 years) and 49% were female; 97% received induction CHEMO for AML. Forty–six patients developed at least one infectious episode from day 1 of chemotherapy until chemotherapy response was assessed (median days to response = 28). Nineteen patients developed bacterial infections, 9 patients developed fungal [2 candidiasis; 3 proven and 4 probable aspergillosis] and 18 patients had clinically but not microbiologically documented infections (cellulitis, pneumonia, neutropenic colitis). Baseline BMIS and serum ferritin were evaluable in 83 and 112 patients, respectively (Table 1).
Median baseline ferritin was significantly higher in patients who developed any infection compare to that of patients without infections (p = 0.018). In addition, patients who developed IFI had higher median baseline ferritin to those without IFI (p=0.039). There were no significant differences in the baseline BMIS between patients without infection and those who developed any infection (p= 0.94) or an IFI (p= 0.71).
Conclusions:

Disclosures
Mattiuzzi: Novartis: Research Funding.
Constitutive Lymphoid Expression of the Nuclear Form of RNase H1 Is Associated with Development of Immature B Cell Lymphomas.
Authors: Sakhuja Kiran B , Gugliotti Lina A , Suzuki Yutaka , Kovalchuk Alexander L , Wang Hongsheng , Shin Dong-Mi , Cerritelli Susana M , Morse Herbert C , Crouch Robert J 
Published: October 2019

Abstract
Abstract 1613
Poster Board I-639
Ribonuclease H1, which cleaves the RNA of RNA/DNA hybrids, plays a vital role in the replication of mitochondrial DNA during mouse embryogenesis, but its contributions to later mammalian development and adult biology are not known. In higher eukaryotes two isoforms of RNase H1, a nuclear form and mitochondrial form, are produced from a single transcript. To investigate the effects of constitutive high level RNase H1 expression, we generated transgenic (TG) mice, strain M27F7, with lymphocyte-specific over-expression of nuclear RNase H1. Transcripts in B cells from TG mice were ∼100-fold higher than in wild type B cells. Although there was no obvious phenotype in young mice, some of the older mice, especially females, developed lymphadenopathy, splenomegaly and mediastinal masses and were diagnosed histologically as having lymphoblastic lymphomas. Cell lines established from the tumors were examined by FACS, gene expression profiling and SKY as well as by FISH for Igh and Myc. By FACS criteria, the tumors were B cell lineage and were arrested at the pre-B to immature stage of differentiation. Expression profiles showed the lines to have increased expression of anti-apoptotic genes and genes promoting cell cycle progression. Chromosomal studies revealed no signs of genomic instability or translocations, although there were trisomies of chromosomes 3 and 15. Myc was structurally intact in all lines. These results suggest that RNase H1 plays a previously unappreciated role in early B cell development and that constitutive overexpression contributes to lymphomagenesis.
This work was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.

Disclosures
No relevant conflicts of interest to declare.
Acute Myelogenous Leukemia Blasts Contribute to a Bone Marrow-Stroma in In Vivo NOD/SCID Mouse System..
Authors: Tashiro Haruko , Shirasaki Ryosuke , Oka Yoko , Sugao Toshihiko , Akiyama Nobu , Kawasugi Kazuo , Shirafuji Naoki 
Published: October 2019

Abstract
Abstract 1621
Poster Board I-647
Aims: Cancer stem cell theory has been developed, and whose precise characteristics have been reported. However, there have been no reports on the differentiation of cancer stem cells into the environmental stromal cells. We reported previously that non-adherent acute myelogenous leukemia (AML) cells were differentiated into myofibroblasts to create a microenvironment for proliferation of AML blasts in vitro. In this report we demonstrate that with severe combined immunodeficiency (SCID) mouse system AML blast cells also convert to myofibroblasts to form stroma in vivo.

Materials and Methods
Bone marrow cells were collected from informed AML (M2) patients who had chromosomal translocation of RUNX1 and ETO, from which mononuclear cells were separated with density-gradient sedimentation method. After discarded an adherent cell-fraction, the non-adherent mononuclear cells were injected to the 3.0 Gray-irradiated non-obese diabetes (NOD)/SCID mouse intravenously. For the inactivation of NK cells, anti-Asialo GM1 antibody was injected intra-peritoneally prior to the transplantation, and on each 11th day thereafter. Blood was collected to monitor Runx1 and ETO fusion transcript, and mice were sacrificed after chimeric mRNA was observed. Bone marrow cells were obtained, and sorted with anti-human CD133 antibody and -CD106 to select AML-derived human stromal myofibroblasts referred to the in vitro data. The isolated positive fraction was further cultured, and the biological and the molecular characteristics were analyzed.

Results and Discussion
When non-adherent AML (M2) blast cells were transplanted to NOD/SCID mice, cells were engrafted after 10 weeks. In murine bone marrow cells human stromal cells were identified, in which RUNX1 and ETO gene was fused with FISH analysis. When the parental AML blast cells were cultured on the expanded AML-derived myofibroblasts, AML cells grew extensively. These results indicate that AML cells can create their own microenvironment for proliferation in vivo.

Disclosures
No relevant conflicts of interest to declare.
The Varicella Zoster Virus Immunoglobulin G and the Varicella Zoster Virus Infection in Children with Cancer Under Chemotherapy.
Authors: Shim Ye Jee , Lee Kun Soo , Choi Yong-Mook 
Published: October 2019

Abstract
Abstract 1648
Poster Board I-674

Purpose
The varicella zoster virus (VZV) is known to be fatal especially for immunocompromised patients receiving chemotherapy for childhood cancer. So we investigated the change of varicella zoster virus immunoglobulin G (VZV IgG) before and during chemotherapy in patients who suffered from chicken pox (CP) or herpes zoster (HZ) to find the relationship between them.

Methods
We reviewed the transition of VZV IgG through medical records in children with cancer who experienced CP or HS during chemotherapy from 1998 to 2008 in Kyungpook National University Hospital, Daegu, South Korea.

Results
We checked VZV IgG not only when they were diagnosed as cancer but also when they were receiving chemotherapy for 66 patients (VZV IgG (+) : VZV IgG (-) = 40 : 26). Among initial VZV IgG positive group, 28 patients showed sustained positive IgG during chemotherapy, and 6 patients underwent the disease (CP : HZ = 1 : 5). On the other hand, 12 patients showed negative IgG while chemotherapy and 8 patients experienced the disease (CP : HZ = 4 : 4). The seronegative group after chemotherapy showed higher morbidity of CP or HZ compare to seropositive group (p=0.011). In the case of VZV IgG negative group at diagnosis, 8 patients presented seroconsersion to positive IgG and they had no disease of VZV. Among them, 18 patients who showed still negative IgG developed 4 (CP : HZ = 2 : 2). All together, the seronegative group revealed the tendency of higher morbidity (p=0.034). We treated them using intravenous acyclovir, and no mortality was observed.

Conclusion
Because of higher frequency of CP or HZ in VZV IgG negative group during chemotherapy, it is important to decide when and for whom to carry out VZV vaccination during chemotherapy through regular VZV IgG checking.

Disclosures
No relevant conflicts of interest to declare.
High-Dose Methotrexate, Rituximab, and Temozolomide (MRT) for Patients with Primary CNS Lymphoma (PCNSL).
Authors: Gerstner Elizabeth R. , Hochberg Fred H , Plotkin Scott R. , Eichler April F. , Batchelor Tracy T. 
Published: October 2019

Abstract
Abstract 1672
Poster Board I-698

Introduction
PCNSL is a rare form of non-Hodgkin lymphoma. High-dose methotrexate (HD-MTX) is the backbone of therapy but uncertainty remains about what additional chemotherapies should be added to HD-MTX to improve response rates.

Methods
After receiving IRB consent, we retrospectively evaluated patients with PCNSL treated at our hospital with combination M/R/T at initial diagnosis or at relapse. Patients were treated in 28-day induction cycles as follows: HD-MTX (8g/m2- dose adjusted based on creatinine clearance) on days 1 and 15; rituximab (375 mg/m2) on days 3, 10, 17, and 24; and temozolomide (150-200 mg/m2) on days 7-11. HD-MTX was given every 2 weeks until complete response (CR) and for 2 additional treatments followed by monthly maintenance treatments for 11 months. Rituximab was given weekly for a total of 8 weeks. Temozolomide was continued for 6 months after CR. Brain MRI was done after every other methotrexate treatment to assess response.

Results
Sixteen patients were treated between February 2006 and August 2009. Ten patients received MRT as first-line therapy at the time of initial diagnosis and 6 received MRT as salvage therapy at first or second recurrence. The median age of newly diagnosed patients was 58 (range 47-76) and of relapsed patients was 60 (range 46-76). CSF cytology was atypical in 5/15 patients who underwent lumbar puncture (4 first-line, 1 relapse). After first-line therapy, there were 9 CRs (median cycles to CR = 3) and 1 PR (patient still receiving induction treatment). After salvage therapy, there were 4 CRs (median cycles to CR = 4) and 2 PRs (both patients died while receiving treatment- 1 from an unrelated myocardial infarction). With a median follow-up of 10.3 months in the first-line group and 7.2 months in the relapse group, only 3 patients have progressed; one of whom had clinical progression after a PR and a second who relapsed in the skin. Treatment was well tolerated with reversible grade 4 transammonitis in 1 patient and grade 3 hematological toxicities in 8 patients. One patient experienced grade 4 thrombocytopenia related to temozolomide requiring dose reduction for subsequent cycles.

Conclusions
Combination MRT is well tolerated and resulted in a promising early response rate. The median number of cycles needed to achieve a CR for patients with newly diagnosed PCNSL was less than the 6 cycles we have previously reported for HD-MTX monotherapy suggesting that adding rituximab and temozolomide is beneficial to patients. This combination warrants further evaluation in larger scale, prospective studies.

Disclosures
Off Label Use: temozolomide and rituximab for PCNSL..
Inhibition of Class I PI3K Isoforms Restores the Sensitivity of Acute Myelogenous Leukemia Cells to Multi-Tyrosine Kinase Inhibitors in the Bone Marrow Microenvironment.
Authors: Shimada Akira , Niu Hongmei , Orwick Shelley , Inaba Hiroto , Rubnitz Jeffrey E , Campana Dario , Baker Sharyn D 
Published: October 2019

Abstract
Abstract 1734
Poster Board I-760
The bone marrow microenvironment can protect leukemic cells from cytotoxic agents, an effect that has been attributed to both soluble- and contact-mediated factors. Recently, we showed that 3 AML cell lines (MV4-11, THP1 and U937) became resistant to 3 promising TKIs (sorafenib, sunitinib and midostaurin) in a coculture model with mesenchymal cells (MSCs) (Shimada A. et al. Proceedings ASH 2008). In the current investigation, we show that 9 primary AML blast samples (including 7 with wild-type FLT3 and 2 with FLT3-interal tandem duplications) were less sensitive to 10 μM sorafenib in coculture with MSCs vs. suspension culture [mean percentage of total annexin V positive cells, 25% (range, 17-32%) vs. 36% (range, 31-47%)]. We explored potential mechanisms of resistance in AML cell lines. No alterations in drug intracellular accumulation, FLT3 receptor expression/phosphorylation, or acquired mutations in the FLT3, NRAS or KRAS genes were observed in AML cells in coculture with MSCs. However, we found that contact with AML cells enhanced the secretion of IL-6, IL-8, and VCAM-1 by MSCs. In parallel, multiple signaling pathways were activated in AML cells by MSCs including PI3K/AKT, STAT, ERK, and NFKB. Sorafenib-induced inhibition of phosphoproteins in the PI3K/AKT and ERK pathways was decreased in coculture vs. suspension culture. We evaluated PI103, a selective and potent inhibitor of class I PI3K isoforms, as a potential strategy to overcome TKI resistance in the microenvironment. In 3 AML cell lines, the antileukemic activity of PI103 in combination with each of the 3 TKIs was enhanced to a greater extent in coculture than in suspension culture, which was associated with more effective inhibition of both phospho-AKT and phospho-p70 S6 kinase. In primary AML blast samples, the combination of 1.0 μM PI103 + 10.0 μM sorafenib induced more apoptosis [mean percentage of total annexin V positive cells, 38% (range, 32-47%)] than either agent alone [sorafenib, 25% (16-32%); PI103, 24% (20-36%)]. In conclusion, inhibition of PI3K/AKT signaling represents a potential treatment strategy to restore TKI sensitivity in the microenvironment.

Disclosures
No relevant conflicts of interest to declare.
Polycomb Group Proteins in Myelodysplastic Syndromes and Its Transformation Into Acute Myeloid Leukemia.
Authors: Shen Hongjie , Chen Zi-Xing , Cen Jiannong , Wang Yuanyuan , He Jun 
Published: October 2019

Abstract
Abstract 1756
Poster Board I-782
The myelodysplastic syndrome (MDS) is a group of clonal blood disorders characterized by refractory cytopenia in peripheral blood, dysplastic cellular morphology in bone marrow, and a high risk of malignant transformation. Recently, expression of BMI1, a polycomb group protein, has been used as an important marker for predicting progression of MDS to acute myeloid leukemia(AML). However the function of BMI1 in MDS is remained unknown. Presently, we have analyzed the expression of SALL4, EZH2, P16 and BMI1 in bone marrow mononuclear cells from 48 newly diagnosed MDS patients and 40 treated MDS patients. Real-time polymerase chain reaction has shown that expression levels of these genes in MDS was frequently higher than that of non-MDS cytopenians (P<0.05). A high level of SALL4 expression in newly diagnosed MDS was always associated with high level of BMI1 expression. When MDS cases were divided into two groups based on their SALL4 mean level, The BMI1 expressed significantly higher in SALL4 higher group than that of SALL4 lower group (P<0.05). The BMI1 expression pattern showed an increasing tendency from MDS-RA moving to MDS-RAEB, without a statistically significance. On the contrary, the EZH2 expression level of MDS-RAEB is lower than that of MDS-RA (P<0.05). Although BMI1 expression level has been down-regulated when MDS patients are in morphological remission, the expression level of SALL4 and EZH2, P16 still remain abnormal (P<0.05). A significantly high level of BMI1 expression could usually be observed in MDS patients in progression, i.e. from RA to RAEB or from MDS to AML. To study whether BMI1 contributes to the MDS progression, we have transfected U937 and K562 cell line with BMI1 full-length cDNA mediated by MSCV retroviral vector and selected subclone cells. The viability of BMI1 transfected cell is much higher than the control cells cultured serum-free medium. Flow cytometry has shown that BMI1 transfected cell also inhibit apoptosis induced by As2O3. By real-time RT-PCR, it was found that BMI1 can repress the expression of EZH2, PTEN and P16 in BMI1 transfected U937 cell line, while only repress the expression of EZH2 in BMI1 transfected K562 cell line. These results suggest that the polycomb group family genes probably play a pivotal role in MDS progression, and BMI1 cooperated with EZH2 may act via an epigenetic mechanism in the pathogenesis of MDS.

Disclosures
No relevant conflicts of interest to declare.
Immunoglobulin D Multiple Myeloma: Clinical Presentation, Response to Therapy and Prognostic Factors in 75 Patients; An Analysis of the Korean Multiple Myeloma Working Party (KMMWP).
Authors: Kim Min Kyoung , Suh Cheolwon , Min Chang-Ki , Kim Seok Jin , Kim Kihyun , Moon Joon Ho , Yoon Sung-Soo , Lee Gyeong-Won , Kang Hye Jin , Kim Sung Hyun , Choi Chul Won , Eom Hyeon Seok , Kwak Jae-Yong , Kim Hyo Jung , Mun Yeung-Chul , Bang Soo-Mee , Lee Keehyun , Shin Ho Jin , Yang Deok Hwan , Lee Jae Hoon 
Published: October 2019

Abstract
Abstract 1792
Poster Board I-818

Purpose
The primary objective of this study was to analyze the clinical and laboratory characteristics, response to therapy, and survival in patients with IgD multiple myeloma. The secondary objectives were to evaluate the efficacy of treatment, including autologous stem cell transplantation, in these patients.

Patients and Methods
Records of 75 patients with IgD multiple myeloma from 18 institutions were reviewed using the Korean Myeloma Registry (KMR) database (www.myeloma.co.kr).

Results
Median patient age was 57 years (range, 34∼81 years) and 67% were male. The main presenting features were bone pain (77%) and fatigue (77%). Thirty patients (40%) had ECOG PS ≥ 2, and 71 (94%) had ≥1 lytic bone lesions. Renal function impairment (sCr level ≥2 mg/dL) and hypercalcemia (sCa level ≥12 mg/dL) were present in 53% and 27% of patients, respectively. Median serum M protein level was 1.4 g/dL, and 89% of patients had lambda light chains. Forty-nine patients (65%) were stage III by the ISS and 92% were stage III by DSS. Forty-nine patients were assessable for chromosomal analysis, 46 by conventional cytogenetics and 3 by FISH analysis. Of these, 23 patients (47%) had chromosomal abnormalities associated with poor prognosis. Thirty-nine patients (52%) were treated with VAD chemotherapy; the 36 patients assessable for response had an objective response rate of 59%. Eighteen patients (24%) received first-line combination chemotherapy including new drugs (bortezomib or thalidomide) and their objective response rate was 88%. At a median follow up of 28.6 months for the surviving patients, the median OS was 18.5 months and median PFS was 10.4 months. Multivariate analysis showed that age ' 65 (vs > 65), absence of extramedullary plasmacytoma, absence of del(13) or hypoploidy and serum beta-2 microglobulin level <8.0 mg/dL (vs ≥ 8.0mg/dL) were significant prognostic factors for OS. Thirty-four patients (45%) underwent SCT, 32 as part of their initial therapy. For patients who received SCT after complete or partial response to initial therapy, the median OS was 30 months.

Conclusion
IgD multiple myeloma is an aggressive disease that is usually detected at an advanced stage. Despite initial response, survival after relapse is dismal. Intensive treatment strategies to induce high quality responses before SCT may improve outcomes in younger patients.

Disclosures
Suh: Janssen Korea: Research Funding.