bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential Role of Heme Oxygenase-1 in Arsenic Trioxide and Hemin-Mediated Differentiation of Human Promyelocytic Leukemia Cells
Authors: Yang Casey , Beckman Joan D , Schmidt Thomas E , Nguyen Julia , Belcher John D , Vercellotti Gregory M. 
Published: April 2020

Abstract
Acute promyelocytic leukemia (APL) is a myeloid-derived leukemia characterized by a block of differentiation at the promyelocytic stage of development. APL is associated with a reciprocal translocation of chromosomes 15 and 17 involving the retinoic acid receptor-alpha (RARα) locus and the promyelocytic leukemia locus (PML) forming a new fusion gene, PML/RARα. The fusion protein prevents the cells from differentiating by repressing transcription of target genes necessary for differentiation. Therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have improved the clinical outcomes in APL. ATRA differentiates APL cells by promoting degradation of PML/RARα and relieving transcriptional repression. ATO induces apoptosis and differentiation of APL cells through separate pathways involving activation of apoptotic pathways and degradation of the PML/RARα protein. The heme-catabolizing protein heme oxygenase-1 (HO-1) which produces carbon monoxide, biliverdin/bilirubin and releases Fe/ferritin can be cytoprotective and anti-apoptotic. HO-1 message and protein are markedly upregulated in response to hemin. ATO also can induce HO-1 expression and has been shown to induce differentiation of leukemic cells. We hypothesize that induction of HO-1 mediates APL differentiation in response to ATO and hemin. We utilized a human APL cell line, NB4, to test our hypothesis in vitro using NBT reduction to assess cell differentiation. ATRA (p &lt; 0.005 at both 72 and 96 hours), ATO (p &lt; 0.005 at 72 hours, and p &lt; 0.05 at 96 hours), and hemin (p &lt; 0.05 at both 72 and 96 hours, n=3) were shown to differentiate NB4 cells compared to untreated groups. RT-PCR indicated HO-1 expression increased in response to ATRA, ATO, and hemin, while biliverdin reductase (BVR), a signaling protein that degrades biliverdin to bilirubin, was only induced by hemin. Inhibition of HO-1 activity with tin-protoporphyrin significantly (p&lt;0.05, n=2) blocked differentiation induced by ATO but had no effect on ATRA–treated cells. We speculate that HO-1 and its downstream metabolic products play critical roles in ATO-induced differentiation of APL cells.
Acute Myeloid Leukemia in Adolescents and Young Adults (AYA): The MD Anderson Cancer Center (MDACC) Experience
Authors: Pemmaraju Naveen , Kantarjian Hagop M. , Ravandi Farhad , O’Brien Susan , Wierda William G. , Thomas Deborah A. , Garcia-Manero Guillermo , Borthakur Gautam , Pierce Sherry , Cortes Jorge 
Published: April 2020

Abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic neoplasms demonstrating clonal proliferation of myeloid precursors and is typically a disease of older adults. In acute lymphoblastic leukemia (ALL) adolescent and young adult (AYA) patients (pts) have a distinct outcome, possibly influenced by type of therapy (i.e., usually better with more intensive regimens). There is little information about outcome of AML in AYA.
Aims: To define the characteristics and outcome of AYA pts with AML treated at MDACC.
Methods: We retrospectively analyzed the data of all pts with AML treated at MDACC from 1965 to 2008. Those aged 16 to 21 years were defined as AYA.
Results: Among 3934 adult pts seen during this period, 163 (4%) were AYA. The median age was 19 yrs. These included 27 (17%) pts with Core Binding Factor (CBF)-AML [inv(16), t (8:21)]and 19 pts (12%) with acute promyelocytic leukemia (APL). Among other evaluable pts, 50% had diploid cytogenetics, 39% miscellaneous changes, and 11% 5-and/or 7- abnormalities. Antecedent hematologic disorders were present in 33 (20%) and AML was a secondary malignancy in 6%. Among 20 evaluable pts, FLT3 ITD was documented in 4 and mutation in 2. CR rates were 89% for CBF AML, 79% for APL, and 75% for all others. The median survival for the total group was 88 weeks (wks) with 36% alive at 3 yrs, and median CR duration of 67 wks (30% CR at 3 yrs). Outcome is better for pts with CBF leukemias (3-yr survival 56%, CR duration 49%) and APL (3-yr survival 51%, CR duration 36%) compared to other AML (3-yr survival 28%, CR duration 24%). CR rates have improved from 71% in 1965–84, to 85% in 1985–94 and 83% after 1994. Similarly, overall survival (OS) has increased during the same time periods (3-yr survival 18%, 44%, and 53%, respectively) together with CR duration (3-yr CR duration 21%, 32% and 39%, respectively) as early mortality has decreased (11%, 8%, and 4%, respectively). To compare outcome with older adults, we focused on those with diploid cytogenetics (Table 1):
Percentage by age group Outcome 16–21 22–45 46–60 &gt;60 CR 81 75 68 54 Induction mortality 2 11 13 24 3-year survival 46 36 28 16 3-year remission duration 39 32 30 22
Conclusion: The outcome of AYA pts with AML is significantly better than that of older adults with AML. Despite these improvements over time, there is still significant room for improvement in this area, particularly among those with AML other than CBF and APL. Exploration of new treatment options is needed in this patient population.
Systemic Delivery of Nanoliposomal Ceramide Displays Anti-Leukemic Activity in a Rat Model of Large Granular Lymphocytic Leukemia
Authors: Liu Xin , Ryland Lindsay , Yang Jun , Aliaga Cesar , Kaiser James , Zhang Ranran , Thomas Kendall , Jarbadan Ruth Nancy , Hughes Joseph , Kester Mark , Loughran Thomas P. 
Published: April 2020

Abstract
We have previously demonstrated that enhanced survival rather than increased proliferation accounts for the accumulation of natural killer (NK) cells in large granular lymphocyte (LGL) leukemia patients. To further elucidate the mechanism by which NK survival is enhanced, we analyzed leukemic NK cells isolated either from patient peripheral blood or rat splenic cells for altered expression of members of the inhibitor of apoptosis protein (IAP) family, which act as suppressors of apoptosis in a variety of human solid tumors and hematological malignancies. We now report that the IAP, survivin, was highly expressed in NK cells. In contrast, survivin was barely detectable in NK cells from the blood of normal human donors or the splenic cells from normal rats. We next asked if the lipid-derived second messenger, ceramide, which selectively induces apoptosis in cancer cells would diminish survivin protein expression. Treatment of NKL, a human NK-LGL leukemia cell line, or RNK-16, a rat NK-LGL leukemia cell line, with the cell-permeable, short-chain C6-ceramide (C6) in a pegylated liposomal formulation, led to cell apoptosis and diminished survivin protein expression, in a time and dose dependent manner. We next extended these in vitro studies to an in vivo rat model of NK-LGL leukemia. Systemic i.v. delivery of liposomal ceramide displayed significant anti-leukemia activity in a syngeneic Fischer F344 rat NK-LGL leukemia model that exhibits clonal expansion of CD3-CD8a+ lymphocytes. Over a 6-week treatment period, a well-tolerated dose of 40 mg/kg liposomal-C6, three times a week, elicited a 3 to 10- fold reduction in the weight of various lymphoid and non-lymphoid organs, compared with liposomal formulations that did not contain ceramide (ghost). Untreated or ghost-treated leukemic rats presented with lymphocytosis (LGL counts between 2 × 1011 and 3.5 × 1011/L), anemia and thrombocytopenia. Furthermore, the percentage of NK LGL cells, defined as CD3-CD8a+ by flow cytometry, was drastically elevated in the spleen, lymph node, thymus, bone marrow, blood, liver and lung in these leukemic rats, compared with their normal counterparts. In contrast, leukemic rats treated with liposomal ceramide had undetectable LGL cells in the blood and normal counts of red blood cells and platelets. Additionally, the CD3-CD8a+ NK cells in spleen, thymus and liver were found to be remarkably decreased, whereas the NK cells in bone marrow, blood and lung were within normal range. Collectively, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for anti-leukemic efficacy in a rat model of NK LGL leukemia, possibly via decreased survivin expression or signaling.
Therapeutic Potential of Small Molecule Inhibitor of Wnt Signaling in Acute Myelogenous Leukemia
Authors: Briaud Isabelle , Tenzin Fnu , Chun Jae Kwang , Oh Se-Woong , Chung Jae Uk , Jung Kyung Yun , Jeong Min Wook , Cha Joo Young , Pyon Younghee , Lee Donghee , Jung Ji Eun , Emami Katayoon H. 
Published: April 2020

Abstract
Wnt signaling pathway controls various cellular and developmental processes. Deregulation of this pathway, in a wide range of human solid tumors, has been well established. However, less is known about its role in etiology of hematological cancers. Some characteristics of acute myelogenous leukemia (AML) cells such as inappropriate proliferation in the absence of normal growth signals and indefinite self-renewal similar to a stem cell are thought to be due to mutations in β-catenin, the hallmark of canonical Wnt pathway, and/or activation of Wnt pathway by fusion transcription factors. For therapeutic purposes, we have screened a peptidomimetic, β-turn library of small molecules for an inhibitor of Wnt pathway. Through massive chemical modifications the lead compound CWP231904 was selected. CWP231904 showed good inhibitory activity in the Reporter Gene Assay (RGA) on Topflash promoter in SW480 and HEK293 cells. Wnt target genes, survivin and c-myc were both down regulated upon CWP231904 treatments at the level of RNA and protein in MV4-11 and HL-60 AML cells. CWP231904 treatments of both cell lines induce cleavage of caspase-3, -8, and -9 by apoptotic signals. Propidium Iodide staining of these cells show dramatic increase in Apoptotic Index. CWP231904 treatment of MV4- 11 and HL-60 cells led to degradation of β-catenin in both cell lines. Proteasome inhibitor, MG132, prevented the CWP231904 induced degradation of β-catenin in MV4-11 cells. In order to unravel the mode of action of CWP231904, we utilized Wnt3a conditioned media (CM) or an overexpressed, Estradiol (ER) inducible Dishevelled plasmid (ER-DVL-2) to activate Wnt signaling in HEK293 cell line. Immunoblotting of HEK293 cells induced with ER and treated with CWP231904 showed a nuclear migration of the phosphorylated form of DVL-2 in treated cells. Thus, our data suggest that CWP231904 targets β-catenin degradation by relocating DVL-2 from cytoplasm where it makes puncta and inactivates GSK-3β containing destruction box complex into the nucleus. Moreover, CWP231904 treatment of HEK293 cells growing in Wnt3a CM lowered the inhibitory phosphorylation of GSK3-β on Serine9 which is induced upon Wnt activation, thereby keeping GSK3-β in its active form to phosphorylate β-catenin and signal it for degradation. CWP231904 significantly reduced tumor growth in MV4-11, HL-60 and MOLM-13 xenograft models, significantly increased the life span of the SCID mice, and decreased the number of CD45+ AML cells in the bone marrow after engraftment of MV4-11 cells via intravenous injection withoutdetectable toxicity. Together, these results suggest that CWP231904 has therapeutic potential for the treatment of AML disease by inhibiting Wnt signaling pathway through destabilization of β-catenin.
Acute Myelogenous Leukemia in the Elderly. Intensive Induction Chemotherapy Improves Survival
Authors: Sharma Anant , Shi Runhua , Turturro Francesco 
Published: April 2020

Abstract
Acute Myeloid Leukemia (AML) in the elderly has poor prognoses and carries inferior results with therapy. The purpose of this study was to determine the incidence of elderly AML, examine clinical outcomes with treatment and investigate the impact of intensive induction chemotherapy and other variables such as such as age, leucocytoses, cytogenetics and presence of antecedent hematologic disorder (AHD) on survival, in a cohort of elderly patients with AML treated at our institution.
Patients and Methods: The retrospective review included all patients (age&gt;59) treated between January 1999 and February 2008. Patients diagnosed with acute promyelocytic leukemia were excluded. Records were reviewed from time of diagnoses till death or last follow-up.
Statistical analyses: Median survival was calculated using Kaplan Meier method and differences in survival between patients treated with intensive chemotherapy and those receiving supportive care were compared using the logrank test which was also used to determine the association between survival and variables such as older age (&lt;69 vs. ≥ 69), leucocytoses (WBC &gt;10k), cytogenetics and history of AHD.
Results: Study cohort included 51 patients with age&gt;59. This represented 29% of all AML cases (n=176) treated at our institution. 31(60.78%) were males. Mean age was 68.42 years, range (60–82) with 23 (45.10%) being &gt;69 years of age. History of AHD was observed in 15 (29.41%). Results of cytogenetic studies were available for 29(56.86%) patients of which 11(37.93%) had poor risk cytogenetics with the remainder falling in the intermediate risk group. Elevated WBC count was seen in 25(49.02%). Intensive induction chemotherapy was administered with an anthracycline and cytarabine regimen to 42(82.35%) patients with an induction mortality of 26%. Total of 23 (54.76%) patients achieved first complete remission (CR1). Of those who achieved CR1, 19(82.60%) underwent consolidation. Median survival was 120 days, range (1–2035). By univariate analyses, survival was not affected by older age (p=0.98), poor cytogenetics (p=0.23) or history of AHD (p=0.59), but was affected by induction chemotherapy (p=0.0001), ability to achieve CR1 (p=0.0001) and elevated WBC (p=0.05). In multivariate analyses after adjusting for other variables risk of death was influenced by ability to achieve CR1 (HR 0.146), AHD (HR=2.66) and elevated WBC count (HR=2.48).
Conclusion: Elderly AML has poor clinical outcomes. Risk of death is reduced by intensive induction chemotherapy and achievement of CR1. It is increased by history of AHD and elevated WBC at presentation.
Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia : Single-Center Experience
Authors: Sung Hwa Jung , Kim Eui Bae , Lee Se Ryeon , Seo Hee Yun , Park Kyong Hwa , Choi In keun , Oh Sang Chul , Choi Chul Won , Kim Byung Soo , Kim Yeul Hong , Kim Jun Suk 
Published: April 2020

Abstract
Background: The results of salvage chemotherapy for patient with refractory or relapsed acute myeloid leukemia(AML) have been generally disappointing with low response rates and occasional long-term survivors in most studies. Since therapeutic failure seems to be inevitable in the great majority of these patients, development of more effective salvage therapy is warranted. Recent approaches to the treatment of previously treated AML generally involved the use of cytarabine in intermediate or high-dose alone or in association with new intercalating agents, such as amsacrine, mitoxantrone or idarubicin, etoposide, or asparaginase.
Methods: A single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for 1 hour, and cytarabine (Ara-C) 1g/m2 IV for 6 hours daily for 6 days (MEC), has been proposed as a salvage regimen. Between October 1998 and May 2005, thirty refractory/relapsed AML patients have been treated by MEC salvage chemotherapy. Twenty two patients were in relapse and eight patients were refractory after conventional induction chemotherapy including cytarabine and idarubicin or mitoxantrone. Two patient were in relapse after allogenous hematopoietic stem cell transplantation(SCT).
Results: Complete remission(CR) was obtained in 12 of 30 patients(40%) and 3 of 30(10%) died during salvage treatment: 2 due to intracranial hemorrhage and 1 due to fungemia sepsis. After CR achievement, 5 patients received consolidation chemotherapy. Two patients with an HLA-identical sibling donor underwent allogeneic SCT, and one patient received autologous SCT. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 90% of patients. Nonhematologic toxicity was minimal. At the time of analysis, 9 of 11 patients who achieved CR have relapsed. Median disease-free survival was 12 months. Median overall survival was 13.5 months. There were only two longterm remitters. Several clinicolaboratory and treatment-related variables were analyzed to determine their prognostic significance for CR achievement, duration of CR, overall survival.
Conclusions: Our results suggest that MEC combination chemotherapy might induce CR in a patient with refractory or relapsed AML, although new agents or new therapeutic strategies should be required for long term remission.
Specific Immune Response Induced by PML-Rarα-hIL-2 Vaccine in BALB/C Mice
Authors: Li Yangqiu , Cen Dongzhi , Zhou Yubing , Yang Lijian , Hu Gang , Chen Shaohua , Lin Chen 
Published: April 2020

Abstract
Specific active immunotherapy with DNA vaccines offers the hope for a natural nontoxic alternative to eradicate minimal residual disease in cancer patients. However, little data are regarding the DNA vaccines in leukemia. Our previous study has successfully developed a vector containing PML-RARα segment fused to human Interleukin- 2 (hIL-2) gene. In the present study, we analyzed the specific immune response by immunization with the recombinant plasmid in BALB/c mice. The recombinant plasmids were injected into BALB/C mice with a total of 200 μg DNA in normal saline at 14-day intervals for three cycles. The plasmid containing the same sequence of PML-RARα segment or hIL-2 gene alone and blank plasmid served as controls. Two weeks after the final DNA boost, the transcription and expression of PML-RARα and hIL-2 in injection site were detected by RT-PCR and immunohistological methods; the specific cytotoxicity of spleen cells from the vaccinated BALB/C mice was detected by LDH release assay; interferon-γ secretion was measured by ELISA; antibodies against human PML-RARα were detected by indirect immunofluorescene analysis (flow cytometry); and T-cell receptor rearrangement excision circles (TRECs) in DNA from mice thymic cells were detected by real-time quantitative RT-PCR (TaqMan), thereby to evaluate the content of naïve T cells. After immunization, the PML-RARα/hIL-2 mRNA and protein could be identified in the injection site of PML-RARα- hIL-2 vaccinated mice. Time dependent antibody production and an increase in INF–γ could be detected in vaccinated mice serum (p&lt;0.05). Specific cytotoxicity on NB4 cells was significantly higher than that from control groups (p=0.012). TRECs level form PML-RARα-hIL-2 vaccine group was significantly higher than that from PML-RARα, hIL-2 vaccine or control groups (p&lt;0.05). In conclusions, the reconstructed PML-RARα plasmids might display the common feature of DNA vaccine, which can induce specific humoral and cellular immune responses in BALB/c mice in vivo and can induce the increase of naïve T cells in mice thymus, it might relate to stronger cellular immune response, it is to our knowledge, the first description on the change of naïve T cells in response to vaccine.
The DNA Crosslinking Agent SJG-136 (SG2000, BN2629) Is Highly Potent in Acute Myeloid Leukaemia and Is Synergistic with Cytarabine
Authors: Walsby Elisabeth J , Burnett Alan , Knapper Steven , Fegan Chris , Pepper Chris 
Published: April 2020

Abstract
Standard treatment of acute myeloid leukemia (AML) results in a median survival of approximately 1 year. However, increased understanding of the complex biology of AML has led to the introduction of more targeted therapies, including gemtuzumab ozogamycin and a number of FLT3 inhibitors, in the expectation that they will improve outcomes in this condition. The future is likely to see combinations of new targeted drugs together with more standard therapies. The challenge will be to identify the optimal combinations for individual patients based on their specific disease markers. SJG-136 (SG2000, BN2629) is a pyrrolo[2,1-c][1,4]benzodiazepine dimer which binds into the minor grove of DNA with a preference for 5′Œ-GATC-3′Œ sequences. The crosslinks that SJG-136 forms are more persistent than those formed by nitrogen mustard agents like melphalan due to their slow rate of repair. We have previously shown that SJG-136 is very potent against primary chronic lymphocytic leukaemia (CLL) cells so we set out to investigate its effect on AML cell lines and primary AML. The AML cell lines, NB4 and HL60, had LD50 values of 5.75nM and 12.10nM respectively following exposure to SJG-136 for 48 hours. Apoptosis induction was dose-dependent, as evidenced by Annexin V/propidium iodide assay and caspase-3 activation assay. Subsequently, primary AML cells from 37 diagnostic samples were isolated and treated with SJG-136 and cytarabine yielding an average LD50 of 19.4nM (±22.8) and 5.7mM (±5.6) respectively. SJG-136 was &gt;100 times more potent than cytarabine in samples derived from the same patients (P&lt; 0.0001). We next investigated the potential for synergy between cytarabine and SJG-136 in the AML cell lines (cytarabine:SJG-136, 100:1). NB4 cells demonstrated a combination index (CI) for the two agents of 0.37 and HL60 cells showed a CI of 0.69 indicating that these two agents were synergistic in the two cells lines under these conditions. The primary AML samples were also tested in vitro for synergy between SJG-136 and cytarabine at the same ratio. In these samples the mean CI was 0.56 (± 0.49) with synergy being demonstrated in 29/37 patient samples. Closer examination of these results showed that the 8 patient samples with a CI greater than 1 were all particularly sensitive to cytarabine as a single agent. Therefore, the increased sensitivity of these patient samples to cytarabine may account for their apparent lack of synergy as calculated by the median effect method. These results indicate that SJG-136 has significant potential as a therapy for AML both as a single agent and in combination with cytarabine.