bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Angiopoietins and Their Receptor Tie2 in the Bone Marrow of Patients with Acute Myeloid Leukemia.
Authors: Schliemann Christoph , Bieker Ralf , Padro Teresa , Kessler Torsten , Hintelmann Heike , Buchner Thomas , Berdel Wolfgang E. , Mesters Rolf M. 
Published: October 2019

Abstract
Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P < 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P < 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P < 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P < 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.
Chimeric Leukemic Protein PLZF/RARα Functions as an Adoptor for Cul3-Based E3 Ubiquitin Ligase To Regulate Proteosomal Degradation of RXRα.
Authors: Onozawa Masahiro , Kondo Takeshi , Kanamori Hiroe , Kahata Kaoru , Hashino Satoshi , Asaka Masahiro 
Published: October 2019

Abstract
Typical acute promyelocytic leukemia (APL) is associated with expression of the PML/RARα fusion protein resulting from chromosomal translocation t(15;17) and responsiveness to treatment with all-trans retinoic acid (ATRA). A few population of APL is associated with variant chromosomal translocations, t(11;17), t(5;17) and t(17;17). PLZF/RARα is the chimeric fusion protein resulting from the chromosomal translocation, t(11;17)(q23;q21). APL cells with PLZF/RARα have been reported to be unresponsive to ATRA-induced terminal differentiation clinically and experimentally. The molecular basis of unresponsiveness in PLZF/RARα-derived APL cells against ATRA explained by a rigid interaction between BTB/POZ domain of PLZF and a transcriptional co-repressor, N-CoR. PLZF/RARα contains BTB/POZ domain in its N-terminus. BTB/POZ domain is developmentally conserved among various species, and recently several BTB/POZ-containing molecules have been reported to function as substrate-specific adaptors for Cul3-based E3 ubiquitin ligase. Here we examined the possibility that PLZF/RARα functions as an E3 ligase.
We performed the series of transient transfection analysis. By immunoprecipitation assay, PLZF/RARα associated with Cul3, and PLZF/RARα also associated with RXRα. PLZF/RARα accelerated an ubiquitin-dependent degradation of RXRα, and resulted in the decreased expression of RXRα. This degradation of RXRα was dependent on the expression level of PLZF/RARα. On the contrary, co-expression of dominant negative form of Cul3 with PLZF/RARα resulted in the restored expression of RXRα. When we expressed PML/RARα, PLZF or PLZF/RARαΔBTB, the accelerated degradation of RXRα was not observed.
In RARα-responsive luciferase assay, PLZF/RARα repressed ATRA response. Consistent with the result that PLZF/RARαΔBTB did not down-regulate the expression of RXRα, PLZF/RARαΔBTB did not repress ATRA response. In addition, the transduction of recombinant RXRα molecule into PLZF/RARα expressing cells partially restored ATRA-responsiveness. Collectively, we suggest that ATRA resistance in PLZF/RARα-positive cells is explained by the novel function of PLZF/RARα molecule.
Physical and Functional Interactions of Acute Myeloid Leukemia-1 with Hypoxia Inducible Factor-1α Protein.
Authors: Yu Yun , Peng Zhen-Gang , Zhou Mei-Yi , Liao Shi-Hua , Huang Ying , Qiu Ji-Hui , Wang Li-Shun , Dong Shuo , Chen Guo-Qiang 
Published: October 2019

Abstract
Hypoxia inducible factor-1α (HIF-1α), a critical transcription factor for cellular responses to hypoxia, was shown to regulate the differentiation of some kinds of tissue cells including acute myeloid leukemic (AML) cells. Based on the important role of AML1 protein in hematopoietic development, this work tries to investigate the potential relationship of AML1 as well as its abnormal leukemogenic fusion protein AML1-ETO with HIF-1α protein. The results showed that HIF-1α protein physically and directly interacts with ectopically and constitutively expressed AML1 or AML1-ETO protein, as evidenced by integrated Lac operator array, co-immunoprecipitation and GST pull-down assay. It appears that AML1-ETO has better binding ability with HIF-1α protein. With this interaction, either AML1 or AML1-ETO attenuates the transcriptional activity of HIF-1α protein with the inhibition of expressions of vascular endothelial growth factor and glucose transporter-1, two well-known HIF-1α-targeted genes. On the contrary, hypoxia-stabilized HIF-1α protein potentiates transcriptional ability of AML1 and AML1-ETO, as assessed by AML1-binding sites-driven luciferase assay. According to these results, a speculative hypothesis is proposed for the dual roles of HIF-1α in leukemic cell differentiation and angiogenesis. The further investigations would open another avenue of attacking against cancer.
MEIS1 Is a Required Transcription Factor for AML Cell Proliferation.
Authors: Heinrichs Stefan , Brenner Chad J. , Kulkarni Rima V. , Thomas Look A. 
Published: October 2019

Abstract
MEIS proteins constitute an important subgroup of three amino acid loop extension (TALE) class transcription factors, which are characterized by an atypical homeodomain. MEIS1 has been shown to act as an important cofactor in HOXA9-mediated leukemogenesis in bone marrow transduction experiments. In human leukemia, MEIS1 was identified as a gene consistently upregulated in leukemias with MLL translocations. However, MEIS1 overexpression is also frequently found in AMLs with normal or complex karyotypes. To investigate the role of MEIS1 in AML pathogenesis, we measured the expression of MEIS1 and MEIS2 in 26 different established human AML cell lines, and documented high levels of expression of one or both genes in 20 of these lines. Despite the prevalence of MEIS1 expression in AML blasts, the downstream pathways and their contribution to the proliferation or self-renewal of the malignant clone are not well understood. To identify gene expression programs controlled by MEIS1, we targeted MEIS1 expression by RNAi in two AML cell lines that express HOXA9 and MEIS1, but only low levels of MEIS2. In comparison to a control shRNA, cells expressing two different MEIS1-specific shRNAs were markedly deficient in thymidine incorporation indicating very low levels of cellular proliferation. The RNAi-mediated knock-down of MEIS1 expression resulted in down-regulation of the tyrosine kinase receptor FLT3 by quantitative RT-PCR. Thus our data in human AML is consistent with results of Wang et al. (Blood, 106(1):254–64) implicating MEIS1 in the regulation of FLT3 tyrosine kinase expression, based on overexpression studies in mouse bone marrow progenitors. Our results in human AML suggest that MEIS1 is required for high levels of FLT3 expression, which is significant because FLT3 is mutated and activated in these two myeloid leukemia cell lines, suggesting the hypothesis that FLT3 is an important component of the pathway through which MEIS1 promotes proliferation. Programmed re-expression of activated FLT3 in AML lines with MEIS knock-down is underway to test whether FLT3 is the essential component acting downstream of MEIS1 expression in AML pathogenesis.
All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.
Authors: Schlenk Richard F. , Dohner Konstanze , Kerz Martina , del Valle Francisco , Heydrich Björn , Schmidt-Wolf Ingo , Pralle Hans , Götze Katharina , Koller Elisabeth , Nachbaur David , Mergenthaler Hans G. , Fiedler Walter , Haase Detlef , Kremers Stephan , Theobald Matthias , Matzdorff Axel , Ganser Arnold , Dohner Hartmut 
Published: October 2019

Abstract
Background: In primary refractory patients the achievement of a response to salvage therapy is of enormous prognostic impact.
Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine based intensive salvage therapy in primary refractory younger patients on clinical outcome.
Methods: Between 1993 and 2006 264 consecutive patients (median age: 48 yrs) were evaluated. All patients had primary refractory AML after one cycle of ICE (idarubicine, cytarabine, etoposide). The different salvage therapies were as follows: from 1993–1998: S-HAM for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11] and HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; from 1998 to 2004 A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; from 2004 up to date: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1].
Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=118, GO-A-HAM n=62, other n=31, or no further therapy n=10. CR-rate according to salvage therapy was GO-A-HAM 49%, A-HAM 34% S-HAM 23%, HAM 14%. Treatment related mortality did not differ between regimens. No CTC-grade 3–5 liver toxicity was seen in patients receiving GO-A-HAM. Logistic regression on the achievement of CR revealed that regimens containing ATRA (odds ratio 2.0, p=0.05) and GO (odds ratio 1.9 p=0.05) were associated with response. 151 of 264 patients have received a stem cell transplantation as consolidation therapy (n=59 MRD, n=79 MUD, n=6 haplo-identical donor, n=7 autologous). The rates of severe veno occlusive disease after transplant was identical (5%) for patients receiving a salvage therapy including GO and those who did not. Survival analysis revealed a significant difference (p= 0.00178) with a median survival of 16.2 months for GO+ATRA, 12.5 months for ATRA versus 7.2 months for the others.
Conclusions: Although retrospective in nature our study suggests that ATRA and GO as adjunct to salvage therapy improves CR rates and survival in primary refractory AML patients.
A Phase 1 Dose-Escalation Study of the Novel Cell Cycle Active Agent SNS-595 in Advanced Leukemias.
Authors: Lancet Jeffrey E. , Karp Judith E. , Havrilla Nancy , Hoch Ute , Silverman Jeffrey , Adelman Daniel , Giles Francis J. 
Published: October 2019

Abstract
SNS-595 is a novel, cell cycle active cytotoxic naphthyridine analog that induces G2 arrest in a variety of preclinical tumor models. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (arm A) or twice weekly x 2 bolus (arm B), in patients with advanced or refractory acute leukemias.
Objectives: The primary objectives were to:establish safety, tolerability, and MTD of SNS-595 given on each schedule,characterize pharmacokinetics (PK) of SNS-595 when given on these schedules.
Secondary objectives were:assessment of clinical activity,exploration of potential biomarkers.
Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (arm A) or days 1, 4, 8, 11 (arm B). Minimum cycle length was 42 days (arm A) and 39 days (arm B). Additional cycles were permitted if patients achieved stable disease or better. The starting dose was 18 mg/m2/d on arm A, and 9 mg/m2/d on arm B and escalated by cohort using a modified Fibonacci schema. PK analyses for SNS-595 were performed on plasma samples collected during cycle 1. Pretreatment peripheral blood and bone marrow aspirate samples were collected for exploratory analyses of the level and functional activity of the DNA damage repair proteins DNA-PK and MSH2.
Results: To date, 21 patients have been enrolled and are evaluable in the live database, including 13 patients assigned to arm A and 8 assigned to arm B, 12 males and 9 females with a median age of 64 years. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease refractory to or relapsed from prior therapy (median 3 prior regimens (range 1–6)). Dose escalation has proceeded to 50 mg/m2/d (arm A) and 19 mg/m2/d (arm B). No dose-limiting toxicities have been observed to date. Non-dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis . Grade 4 neutropenic fever was observed in only one patient. Plasma exposures at the first two dose levels in each arm increased linearly, resulting in AUCs of 5.5 – 17.8 ughr/mL for 9–27 mg/m2 doses. CL, Vss, and terminal half-lives were similar to those reported previously in solid tumor patients, and averaged ~2 L/hr/m2, 58 L/m2, and 23 hr, respectively. No patients have achieved complete response to date, although 6 patients (distributed across all dosing groups) experienced >50% reductions in peripheral blasts following cycle 1.
Conclusion: SNS-595 appears to be well-tolerated in patients with advanced leukemias, with preliminary and promising signs of clinical activity as measured by decreases in leukemic blasts. Bone marrow ablation has not yet been achieved; patient accrual and dose-escalation are ongoing.
Intensification of Induction by High-Dose AraC and Outcome in Older Patients with De-Novo Acute Myeloid Leukemia (AML) and Subsets.
Authors: Buchner Thomas , Berdel Wolfgang E. , Schoch Claudia , Haferlach Torsten , Tchinda Joelle , Schnittger Susanne , Kern Wolfgang , Reichle Albrecht , Staib Peter , Serve Hubert L. , Ludwig Wolf-Dieter , Sauerland Maria Cristina , Heinecke Achim , Josef Wormann Bernhard , Hiddemann Wolfgang 
Published: October 2019

Abstract
As recently reported modifications, dose or duration of treatment had no impact on outcome of AML in older patients (Burnett et al. Blood 106: 162a, 2005). We therefore evaluated 764 patients 60 years of age or older and their various prognostic subgroups in the 1992 and 1999 mulitcenter randomized trials by the German AMLCG where patients received uniform postremission consolidation by one course of TAD (standard dose thioguanine, araC, daunorubicin) and maintenance by monthly 5 day courses of reduced TAD. For maximum homogeneity this analysis was restricted to de-novo AML and to patients with known karyotype. Before treatment started, patients were assigned to induction treatment by either TAD followed by HAM (HAM, high-dose araC 1g/m2x6 / mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. The second induction course (HAM) was given to only patients with 5% or more residual bone marrow blasts. Therapy administered to the two randomized groups differed by a factor 2 in their araC dose. Despite this difference in treatment intensity patients in the two arms show similar response rate, overall survival (OS), ongoing CR, and relapse-free survival (see table). The same similarity in outcome as for de-novo AML overall is true for established prognostic subgroups as listed below.
Conclusion:
Intensification of induction therapy by high-dose araC has no effect on outcome in older age de-novo AML. Since potential influences other than the randomized treatment were minimized, present results do not support a risk adapted intensification strategy.
TAD-HAM HAM-HAM P TAD-HAM HAM-HAM P OS 4y % OS 4y % CR 4y % CR 4y % Total 18 13 .28 22 22 .53 Favorable Karyotype 17 16 .48 41 33 .82 Intermediate Karyotype 24 18 .31 24 26 .38 Unfavorable Karyotype 4 - .81 - - .37 LDH ≤ 700U/L 21 13 .86 23 24 .47 LDH > 700U/L 12 10 .07 - 16 .27 WBC ≤ 20x103/ccm 21 11 .91 22 21 .81 WBC > 20x103/ccm 15 16 .08 22 26 .19 Day 16 Blasts < 10% 26 16 .87 23 22 .81 Day 16 Blasts ≥ 10% 14 8 .28 18 19 .26
Prospective Multicenter Study for Patients with Therapy - Related Acute Myeloid Leukemia (AML) Using Intensive Induction and Postremission Therapy.
Authors: Wormann Bernhard Josef , Schoch Claudia , Reichle Albrecht , Staib Peter , Ludwig Wolf-Dieter , Sauerland Maria Cristina , Heinecke Achim , Berdel Wolfgang E. , Hiddemann Wolfgang , Buchner Thomas 
Published: October 2019

Abstract
Therapy - related acute myeloid leukemia (t-AML) is one of the most severe long - term complications of successful cancer treatment using chemo- and/or radiotherapy. Its frequency is increasing, also in patients with autoimmune disease after cytostatic therapy. Cytogenetic and molecular biological analysis have identified several subgroups, however large prospective trials on optimal treatment are lacking. In 1999 the German AMLCG started a prospective multicenter randomized trial including patients with t-AML. Patients received induction treatment, randomized to either TAD (standard dose thioguanine, araC, daunorubicin) followed by HAM (HAM, high-dose araC 1 or 3 g/m2x6/mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. Above the age of 60 years, the second induction course was given only to patients with 5 % or more residual bone marrow blasts. Postremission therapy was randomized to either TAD followed by three year maintenance, or to autologous stem cell transplantation. Patients under the age of 60 years with a suitable donor received an allogeneic stem cell transplantation. 137 patients were included. The most frequent primary diagnoses were breast cancer (n = 43), Non Hodgkin’s lymphoma (n = 18), Hodgkin’s lymphoma (n = 9), autoimmune disease (n = 9), multiple myeloma (n = 5), germ cell tumor (n = 5) and ovarian cancer (n = 5). The median age was 57 years (23 – 77). 64 of 119 currently evaluable patients achieved CR (53,8 %), 34 (29 %) had persistent leukaemia, 20 (17,1 %) were classified as early death without evidence of disease. The CR rate was significantly lower than in 1532 patients with de novo AML (65,6 %), but higher than in patients with AML after MDS (46,8 %). Cytogenetic analysis was routinely performed in all patients with t-AML. 21 (17,7 %) had a favourable karyotype, 47 (39,5 %) an unfavourable karyotype, 51 (42,9 %) were classified as intermediate. Patients with favourable karyotype had a median survival of 25 months and an estimated survival rate at 5 yrs of 47,4 %. Median survival was 3 months for patients with unfavourable karyotype with an estimated survival rate of 12,5 %, while the intermediate group had a median survival of 19 months and an estimated survival rate of 24,2 %. This is one of the largest prospective studies on the therapy of patients with t-AML. The CR rate of all patients was inferior to patients with de novo AML. However, this difference was mainly due to the high number of patients with unfavourable karyotype. Within cytogenetically defined subgroups, the prognosis of t-AML patients does not differ significantly from patients with de novo AML.
All-Trans-Retinoic Acid (ATRA) Induces Autophagy in Acute Promyelocytic Leukemia Cells.
Authors: Ozpolat Bulent , Akar Ugur , Kondo Yasuko , Lopez-Berestein Gabriel 
Published: October 2019

Abstract
All-trans-retinoic acid (ATRA), a naturally occurring derivative of vitamin A (retinol), is a potent inducer of cellular differentiation, growth arrest, and apoptosis in various tumor cell lines. ATRA induces terminal differentiation of immature leukemic promyelocytes into normal mature granulocytes in vitro and in vivo, leading to a complete remission in majority of acute promyelocytic leukemia (APL) patients. Thus, this system provides an excellent in vitro model for studying the molecular events taking place during the terminal differentiation of myeloid cells. Apoptosis (type I) and autophagy (type II) are both highly regulated forms of programmed cell death and play crucial roles in such physiological processes as the development, homeostasis and elimination of unwanted cells. In contrast to apoptosis, autophagic cell death is caspase-independent and does not involve classic DNA laddering. Recent studies suggest that cancer cells in general tend to undergo less autophagy than their normal counterparts, supporting the contention that defective autophagic cell death plays a role in the process of carcinogenesis. The present study provides the first evidence that ATRA induces autophagy in acute promyelocytic leukemia cells. We demonstrated that treatment of APL (NB4) cells with ATRA resulted in a marked increase in formation of the acidic vesicular organelles demonstrated by acridine orange staining detected by flow cytometry. ATRA treatment caused about 12-fold increase in number of acridine orange positive cells compared to untreated group. Furthermore, ATRA induced marked upregulation of microtubule-associated protein light chain 3 (LC3-II), an important hallmark of autophagy, by western blot analysis. To determine the mechanim by which ATRA induces autophagy we examined expression of Beclin-1, an autophagy-inducing protein, and Bcl-2, an inhibitor of Beclin-1 as well as levels of mTOR, a suppressor of autophagy, upon ATRA treatment. ATRA inhibited Bcl-2, upregulated Beclin-1 expression and reduced induction of activation/phosphorylation of mTOR in NB4 cells. However, rapamycin, a specific inhibitor of mTOR failed to induce autophagy, suggesting that ATRA-mediated autophagy was independent of the mTOR pathway. We are currently testing whether inhibition of Beclin-1 can prevent ATRA-induced autophagy in APL cells. In conclusion, our results revealed that ATRA plays a role in regulation of autophagy by reducing Bcl-2 and inducing protein Beclin-1, which in turn induces autophagy, suggesting a novel action and mechanism of ATRA in regulation of autophagy in APL cells.