bluuebunny/crossref_metadata_2025_split huggingface dataset:
PKC412 Inhibits the ZNF198-FGFR1 Fusion Tyrosine Kinase and Is Efficacious in Treatment of t(8;13)(p11;q12) Associated Stem Cell Myeloproliferative Disease.
Authors: Chen Jing , DeAngelo Daniel J. , Kutok Jeffery L. , Williams Ifor R. , Lee Benjamin H. , Wadleigh Martha , Duclos Nicole , Cohen Sarah , Adelsperger Jennifer , Okabe Rachel , Coburn Allison , Galinsky Ilene , Huntly Brian J.P. , Cohen Pamela , Meyer Thomas , Fabbro Doriano , Banerji Lolita , Griffin James D. , Xiao Sheng , Fletcher Jonathan A. , Stone Richard M. , Gilliland D. Gary 
Published: October 2019

Abstract
Human stem cell leukemia-lymphoma syndrome usually presents as a myeloproliferative disease (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase. Current empirically-derived cytotoxic chemotherapy is inadequate treatment of this disease. We hypothesized that small molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLCγ, STAT5 and PI3K/AKT, required the proline-rich, but not the zinc-finger domains of ZNF198. A small molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1 induced myeloproliferative disease. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disease with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.
FLT3 Expression Is Increased by MEIS1 and Collaborates with NUP98-HOX Fusion Genes in the Induction of Acute Myeloid Leukemia.
Authors: Palmqvist Lars , Pineault Nicolas , Argiropoulos Bob , Wan Adrian , Humphries Keith R. 
Published: October 2019

Abstract
The TALE family member and HOX cofactor MEIS1 is important in leukemic transformation. MEIS1 has, although non-leukemogenic on its own, been shown to strongly collaborate with several HOX genes and NUP98-HOX fusions to induce acute myeloid leukemia (AML). We have recently described a novel in vitro culture system of cell lines established from murine primary bone marrow cells transduced with the AML-associated fusion gene NUP98-HOXD13 or an engineered NUP98-HOXA10 fusion. These pre-leukemic NUP98-HOX cell lines are transplantable and can efficiently be converted into AML-inducing cells upon MEIS1 transduction. Conveniently, the MEIS1 transduced cells can be purified and preserve their leukemogenic potential even after extensive in vitro expansion. Thus, the availability of the NUP98-HOX cell lines system provided the opportunity to investigate and characterize the mechanism of MEIS1-mediated AML-conversion. Potentially interesting target or candidate genes were screened for expression changes between the parental pre-leukemic lines and AML-inducing MEIS1 transduced cell lines with quantitative RT-PCR and Western blotting. Aberrant expression or mutations of the receptor tyrosine kinase FLT3 gene is a common finding in human AML. Interestingly, Flt3 was found induced 5 to 10 fold in MEIS1 transduced cell lines compared to the parental cell lines. The observed increase in Flt3 expression provided the MEIS1 transduced cells with Flt3 ligand driven growth. This was not seen in the parental cell lines, which could not proliferate with Flt3 ligand as single cytokine or with a MEIS1-homeodomain mutant expressing cell line. Importantly, the Flt3 inhibitor AG1295 could block the proliferative effect of the Flt3 ligand in the MEIS1 transduced cell lines. To test whether Flt3 could substitute for MEIS1-mediated induction of AML in NUP98-HOX pre-leukemic cells, a NUP98-HOXA10 cell line was transduced with an MSCV-Flt3-IRES-YFP construct. The resulting Flt3-transduced cells were shown to express Flt3 at levels similar to that of MEIS1 transduced cells without any significant increase in endogenous Meis1 expression. Transplantation of these cells into mice led to lethal and transplantable AML with a median disease onset of 116 days (n=8) compared to 59 days for MEIS1 (n=4), whereas control transplants remained healthy (n=2). In conclusion, this study demonstrates that MEIS1 can induce Flt3 expression and that Flt3 can collaborate with NUP98-HOX fusion genes in the induction of acute myeloid leukemia. Furthermore, theses results suggest a model in which the leukemogenic synergism of MEIS1 on HOX-mediated leukemia might in part be mediated through FLT3-dependent pathways.
The Dimerization Domain and C-Terminal NCoR/SMRT Interacting Zinc-Finger Domain of t(8;21) Fusion Protein AML1-ETO Have Critical and Opposite Effects on Leukemogenesis.
Authors: Yan Ming , Kanbe Eiki , Peterson Luke F. , Boyapati Anita , Hines Robert , Zhang Dong-Er 
Published: October 2019

Abstract
Previous analyses demonstrated that full length AML1-ETO requires additional mutagenic events to promote leukemia. Here we describe a novel shorter form of the AML1-ETO fusion protein (AML1-ETOtr), which lacks C-terminal NHR3 and NHR4 [NCoR/SMRT interacting zinc-finger (ZnF)] domains. Unlike full length AML1-ETO, expression of AML1-ETOtr results in rapid development of acute myeloid leukemia (AML) in mice. Interestingly, naturally occurring alternatively spliced AML1-ETO variants exist in t(8;21) AML patient samples. AML1-ETOexon9a that includes one additional exon Exon 9a and AML1-ETOintron5 that uses a polyadenylation signal in Intron 5 are two such variants. AML1-ETOexon9a is structurally similar to AML1-ETOtr. AML1-ETOintron5 lacks the NHR2 heterodimerization domain as well as missing the NHR3 and NHR4 domains. To elucidate their putative role in leukemia development, we performed retroviral transduction and transplantation experiments with AML1-ETOexon9a, AML1-ETOintron5, and two zinc-finger domain (NHR4) mutants [AML1-ETOdZnF (deleted ZnF) and AML1-ETOmZnF (mutated ZnF)]. All of the mice transplanted with AML1-ETOexon9a (n = 8), AML1-ETOdZnF (n = 7), and AML1-ETOmZnF (n = 12) expressing cells rapidly developed AML, displaying a similar phenotype to AML1-ETOtr. None of AML1-ETOintron5 (n = 8) mice showed leukemia. These results suggest that the NHR2 domain of AML1-ETO is required whereas the NHR4 NCoR/SMRT interacting zinc finger domain is inhibitory for leukemia development. These observations suggest a novel mechanism of leukemogenesis for the AML1-ETO gene that can transcribe both tumor suppressive and/or oncogenic chimeric protein(s) by alternative RNA splicing.
Vaccination with the PR1 Leukemia-Associated Antigen Can Induce Complete Remission in Patients with Myeloid Leukemia.
Authors: Qazilbash Muzaffar H. , Wieder Eric , Rios Rosa , Lu Sijie , Kant Shreya , Giralt Sergio , Estey Elihu H. , Thall Peter , de Lima Marcos , Couriel Daniel , Champlin Richard E. , Komanduri Krishna , Molldrem Jeffrey J. 
Published: October 2019

Abstract
BACKGROUND: Several studies have established the PR1 peptide (VLQELNVTV) as a human leukemia-associated antigen. PR1 is derived from proteinase 3, an aberrantly expressed protein in myeloid leukemia cells, and can be presented on HLA-A2 to cytotoxic T lymphocytes (CTL) that preferentially kill leukemia over normal hematopoietic progenitors.
METHODS: Thirty-five HLA-A2+ patients with AML, MDS and CML were vaccinated with the PR1 peptide in an incomplete Freund’s adjuvant (Montanide ISA-51) and 75 mg of GM-CSF. Eligibility included AML with smoldering disease or ≥ 2nd CR, CML not responding to upfront treatment or relapsed disease, and MDS with ≥ 5% blasts. Patients were assigned at random to receive 0.25 mg, 0.50 mg, or 1.0 mg PR1 SQ every 3 weeks for 3 total injections. Immune responses (IR) were assessed by PR1/HLA-A2 tetramer staining and intracellular IFN-γ production by CTL, and clinical responses were assessed by bone marrow biopsy before study entry and 3 weeks after the 3rd vaccination.
RESULTS: Thirty-five patients with a median age of 50 (26–82) were treated at a median of 26 months from time of diagnosis, and follow up was 1 to 4 years. Toxicity was limited to grade 1 and 2 injection site reactions. Overall survival was 33% at 4 years. Immune responses (IR) were elicited in 20 of 33 evaluable patients (60%). Of 16 patients with relapsed or refractory AML, there were 4 (25%) clinical responses (3 CR, 1 PR). All 4 AML patients treated during CR remain in CR. Of 10 CML patients, there was 1 cytogentic CR. Three CML patients refractory to allogeneic transplant, interferon and imatinib had stable disease with some hematological improvement since these patients were able to discontinue hydroxyurea and anagrelide. Of 5 MDS patients, there was 1 PR (17% blasts reduced to 4%). Overall survival at 4 years was 14 of 20 patients with IR vs. 0 of 13 without IR (p < 0.0001). Progression-free survival for patients with or without IR was 6.4 months vs. 2.4 months, respectively (p = 0.003).
CONCLUSION: PR1 peptide vaccination is safe and can elicit both immunological and clinical responses in patients with refractory and relapsed myeloid leukemia, which improves progression-free survival of patients with IR to PR1. This is the first study to show complete molecular remission induced by peptide vaccination. These results warrant further study of immunization strategies in the treatment of leukemia.
Inhibition of Breast Cancer and Leukemia Cell-Induced Endothelial Angiogenesis by Low Molecular Weight Heparins (LMWH).
Authors: Marchetti Marina , Vignoli Alfonso , Pagnoncelli Marcella , Falanga Anna 
Published: October 2019

Abstract
Background: Clinical studies have suggested a survival advantage associated with LMWH administration in cancer patients. Angiogenesis is an important step in tumor progression and it has been demonstrated that LMWH can affect in-vitro vessel growth induced by purified proangiogenic factors.
Objective: In this study we investigated whether two different LMWHs, enoxaparin (ENX) and dalteparin (DLT), and unfractionated heparin (UFH), were able to counteract the tube formation capacity of human microvascular endothelial cells (HMEC-1) induced by tumor cell conditioned media (TCM) or by purified factors (i.e. VEGF, bFGF, TNF-alpha and IL-1beta).
Methods: TCM were obtained after a 24h growth from three breast cancer cell lines, i.e. MCF-7, ZR75.1 and MDA.MB.231, and one human promyelocytic leukemia cell line, i.e. NB4 cells. HMEC-1 cells were resuspended in TCM or purified cytokine solutions in the presence or absence of 10 IU/ml heparins (DLT, ENX or UFH) and then seeded in a 96-well plate pre-coated with growth factor-reduced Matrigel. After 24h, tube formation was examined under phase-contrast microscopy and tube length determined by image analysis software. To characterize TCM cytokine contents, TCM were first screened for their VEGF, bFGF, TNF-alpha and IL-1beta levels by ELISA, and then inhibition studies were performed by pre-incubating TCM with specific neutralizing antibodies directed against each of these factors.
Results: TCM from all 4 tumor cell lines induced a significant (p<0.05) increase in total tube length (60 to 95% mean increase) compared with control TCM. Purified proangiogenic factors significantly (p<0.05) promoted tube formation (46 to 68% mean increase), although to a lesser extent than TCM. Angiogenesis induced by each TCM was significantly affected (76 to 100% mean inhibition) by ENX and DLT, but was less sensitive to UFH. A similar pattern of inhibition was observed with tube formation induced by purified angiogenic factors, particularly the angiogenesis induced by VEGF, bFGF, TNF-alpha or IL-1b was 100% inhibited by ENX and 65–75% by DLT, whereas minor or no inhibition was observed with UFH (VEGF= 27%; bFGF = 0%; TNF-alpha= 53%; IL-1beta= 53%). Inhibition studies with neutralizing MoAbs against proangiogenic factors demonstrated that anti-VEGF MoAb was the most effective in inhibiting tube formation induced by both breast cancer and leukemic cells (77 to 84% mean inhibition).
Conclusion: Our data indicate that heparins can inhibit the proangiogenic stimulus of both tumor cells and purified angiogenic factors on microvascular endothelium, and that the LMWHs are more effective than UFH in this experimental system.
Reduced Plasma Fibronectin Leads to Delayed Thrombus Growth in the Injured Arterioles in Vivo.
Authors: Matuskova Jana , Cambien Beatrice , Piffath Crystal , Wagner Denisa D. 
Published: October 2019

Abstract
In addition to von Willebrand factor and fibrinogen, plasma fibronectin (pFN) contributes significantly to thrombus development in arteries. Complete deficiency of plasma fibronectin (in pFN conditional knockout mice) affects thrombus formation and growth and subsequent occlusion of injured arterioles in vivo. We wanted to study a more physiological decrease of plasma fibronectin without having to induce interferon production in the mice to excise the FN gene. Reduced pFN levels are common in patients with liver disease, sepsis and following trauma or surgery. To evaluate the effect of a reduced amount of plasma fibronectin on thrombus formation at arterial shear rate, we used the ferric chloride model of arterial injury in fibronectin heterozygote mice which have 50% of the normal plasma level of FN. Two groups of mice were observed by intravital microscopy - FN heterozygote (FN+/−) and corresponding age matched wild-type controls (FN +/+). The reduced level of pFN did not affect the early platelet interaction with subendothelium but caused a delay of several minutes in appearance of the first thrombus in the injured arteriole (15 min in FN +/− vs 6 min in FN+/+, p<0.001). Although the thrombi were stably anchored to the vessel wall, the growth of the thrombus was slowed down because of the constant platelet shedding in fibronectin heterozygote mice. Consequently, this lack of firm adhesion of the platelets led to occlusion delay (36 min in FN +/− vs 28 min in FN+/+, p<0.01) with the majority of arterioles in the FN+/− mice not occluding by 40 minutes after injury. In conlusion, the phenotype of thrombosis in the mice with 50% of normal pFN level strikingly resembles the phenotype observed in mice with induced complete deficiency of pFN. This further emphasizes the fundamental role of this plasma protein in thrombosis in vivo in the arterial system.
Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Induces Long-Term Responses in Patients with Relapsed or Refractory Follicular Lymphoma (FL).
Authors: Schilder Russell J. , Witzig Thomas E. , Flinn Ian , Gordon Leo I. , Emmanouilides Christos , Wang Hua , Vo Katie , Molina Arturo 
Published: October 2019

Abstract
Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized.
Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients.
Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates.
Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.
The Anti-CD30 Monoclonal Antibody SGN-30 Inhibits Hodgkins Disease Growth and Sensitizes Cells to Established Chemotherapeutics.
Authors: Cerveny Charles G. , Law Che-Leung , McCormick Renee S. , Lenox Joel S. , Hamblett Kevin J. , Westendorf Lori E. , Yamane Andrew K. , Petroziello Joseph M. , Francisco Joseph A. , Wahl Alan F. 
Published: October 2019

Abstract
SGN-30, a chimeric monoclonal antibody with apoptotic-signaling activity against CD30-positive malignancies, is currently in Phase II clinical evaluation against anaplastic large cell lymphoma and Hodgkin’s disease (HD). Mechanisms underlying SGN-30’s anti-tumor activity were evaluated using cDNA array analysis of SGN-30-treated L540 HD cells. Changes in expression of growth and apoptotic related genes including cyclin D2 and p21CIP1/WAF1 followed treatment of L540 and L540cy cells with SGN-30. Intra-cellular staining showed increases in both activated caspase-3 and p21CIP1/WAF1 in L540cy. These alterations coincided with increased Annexin V/PI staining. In addition to directly inducing apoptosis, SGN-30 mediated alterations in gene expression and could sensitize cells to standard chemotherapeutics. To evaluate this potential, L540cy cells were treated for 24 h with SGN-30 followed by exposure to a panel of chemotherapeutics commonly used in HD therapy and the combinations quantified by the Combination Effects method. Most of the chemotherapies examined were at least additive or better in combination with SGN-30, with bleomycin producing the strongest synergistic response. In vitro data were confirmed by the significantly increased efficacy of SGN-30 and bleomycin against established L540cy HD tumor xenografts in SCID mice. Results suggest that in addition to direct cell killing, SGN-30 binding to CD30 on HD tumor cells effects both growth arrest and drug sensitization by altering gene expression of cell cycle and apoptotic-related genes. Importantly, tumor cell sensitization to established chemotherapies, in particular DNA damaging agents used to treat HD, suggests that SGN-30 could improve the outcome of current drug-based therapies for treating HD.
CXCR4-Dependent Repulsion of Mature Single-Positive CD4 Cells Mediates Emigration from Thymus.
Authors: Vianello Fabrizio , Kraft Paul , Hart William , Mok Ying Ting , Poznansky Mark C. 
Published: October 2019

Abstract
Developing thymocytes undergo maturation during their passage through the cortex to the medulla of the thymus before emigrating to peripheral lymphoid organs. Chemokines control T cell migration within and away from the thymus. We have previously shown that the chemokine SDF-1, produced by thymic stroma, repels mature thymocytes away from thymus via a CXCR4 mediated mechanism. We proposed that CXCR4 plays a specific role in thymic emigration. We evaluated the emigration of mature thymocytes away from thymus in a modified fetal thymic organ culture (FTOC) system in fetal thymi from CXCR4+/− (Control) and CXCR4 −/− (KO) mice at day 15.5. Fetal thymic emigrants were collected using a transwell system with a polycarbonate membrane (3 μm pore size). The immunophenotype of thymic emigrants was distinct from that of thymocytes resident in the thymus in both control and CXCR4-KO thymi. From day 9 of culture onwards, only mature SP cells were able to move away from thymus into the lower chamber of the transwell. Only SP CD4 thymocytes expressing CD62Lhigh were found among emigrants, whereas two distinct populations of SP CD8 cells expressing CD62Lhigh and CD62Llow were present in the emigrant fraction. Incubation of FTOC with pertussis toxin significantly inhibited emigration of mature SP thymocytes out of the thymus in control CXCR4 mice (p=0.002). The total number of emigrants collected from CXCR4-KO thymi was always significantly reduced compared to emigrants from control thymi. In addition, the total number of SP CD4 emigrants from CXCR4-KO thymi were strikingly reduced in comparison to control SP CD4 emigrants (p=0.035). There was no statistically significant difference in the maturation of intrathymic thymocytes from CXCR4-KO as compared to control FTOC. Analysis of CD62L expression in CXCR4-KO thymocytes showed retention of SP CD4 cells in the thymus with the immunophenotypic characteristic normally associated with recent thymic emigrants (p<0.05). Treatment of FTOC with the specific CXCR4 antagonist, AMD3100, significantly increased the total number of SP CD4 cells retained in the thymus compared to untreated FTOC (p=0.002). Treatment with AMD3100 significantly reduced the absolute number of emigrants compared to untreated FTOC (p=0.015) and again SP CD4 cells were most affected in their ability to migrate away from the thymus. Treatment of FTOC with sphingosine-1-phosphate (S1P) resulted in an increase in the emigration of SP CD4 cells from CXCR4-KO thymi (p=0.02). In conclusion these data support the view that CXCR4-mediated repulsion of mature thymocytes away from the medullary chemokine SDF-1, termed fugetaxis, is a key mechanism controlling T cell egress from the thymus. These data support the existence of a CXCR4 dependent mechanism governing thymic emigration which may itself have S1P dependent and/or independent components.