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Kenta Yagi, Akira Shimada, Toshiaki Sendo
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown...
February 16, 2018: European Journal of Pharmacology
Mark Reinwald, Jose T Silva, Nicolas J Mueller, Jesús Fortún, Christian Garzoni, Johan W de Fijter, Mario Fernández-Ruiz, Paolo Grossi, Jose María Aguado
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family...
February 15, 2018: Clinical Microbiology and Infection
Shuyuan Lyu, Ming Zhang, Yunxia Gao
RATIONALE: Leukemia is a common hematologic disease that causes various systemic complications, such as ophthalmological disorders. The venous congestion is considered to be the main clinical sign that occurs during the initial stage of the disease, whereas white-centered hemorrhages are the most typical manifestations in leukemic retinopathy. These complications usually manifest when the disease presents with clinical and hematological symptoms. In the present study, we report a patient who was diagnosed with leukemic retinopathy...
February 2018: Medicine (Baltimore)
Vicki Xie, Daochen Tong, Craig T Wallington-Beddoe, Ken F Bradstock, Linda J Bendall
Background: Sphingosine kinase (SphK) 2 has been implicated in the development of a range of cancers and inhibitors of this enzyme are currently in clinical trial. We have previously demonstrated a role for SphK2 in the development of acute lymphoblastic leukemia (ALL). Methods: In this and our previous study we use mouse models: in the previous study the disease was driven by the proto-oncogene BCR/ABL1, while in this study cancer risk was elevated by deletion of the tumor suppressor ARF...
2018: Biomarker Research
Kathy Allen-Proctor, Elizabeth Ruckdeschel, Rana Naous
Chronic myeloid leukemia (CML) is a hematologic malignancy associated with increased circulating myeloid cells and platelets in the peripheral blood, with accompanying bone marrow hyperplasia. The Philadelphia chromosome, t(9;22)(q34;q11), is present in 95% of CML patients, resulting in constitutive tyrosine kinase activity; however, ~5% of CML patients possess a Philadelphia variant. A novel three-way Philadelphia translocation variant, t(9;22;17)(q34;q11.2;q11.2), was identified in a 54-year old man who presented with leukocytosis, anemia and thrombocytosis that was diagnosed with chronic myeloid leukemia, chronic phase...
February 2018: Molecular and Clinical Oncology
Tatsuro Jo, Kazuhiro Noguchi, Shizuka Hayashi, Sadaharu Irie, Risa Hayase, Haruna Shioya, Youhei Kaneko, Kensuke Horio, Jun Taguchi
Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib are primarily used in the initial treatment of chronic phase (CP)-chronic myeloid leukemia (CML), as CMLs harbor the BCR-ABL fusion product. An increased number of lymphocytes and large granular lymphocytes (LGLs) have been observed in patients treated with dasatinib, but not other TKIs. The LGLs have been reported to be primarily natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In the present study, a CP-CML patient who has maintained molecular response 5 for >2...
March 2018: Oncology Letters
Haodong Cai, Li Yang, Kefeng Shen, Wei Zhang, Jie Xiong, Meilan Zhang, Xia Mao, Ying Wang, Min Xiao
E14a3 breakpoint cluster region (BCR)/ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL) fusion transcript is rare in Philadelphia chromosome positive disease, particularly in acute lymphoblastic leukemia (ALL). Recently an e14a3 fusion transcript was detected by multiple laboratory examinations, and the patient was suffering from ALL. Except for the BCR/ABL fusion gene, in the present study the patient additionally had an IKAROS family zinc finger 1 deletion which, has been confirmed as a significant adverse prognosis factor...
February 2018: Oncology Letters
Betül Koçkan, Tayfur Toptaş, Işik Atagündüz, Ayşe Tülin Tuğlular, Ayşe Özer, Mustafa Akkiprik
The present study aimed to detect the frequency of kinase domain (KD) mutations in order to evaluate their clinical significance and functional importance in 45 patients with chronic myeloid leukemia (CML) who were resistant to imatinib therapy. Sanger sequencing was used (45 patients), along with allele-specific oligonucleotide polymerase chain reaction (ASO-PCR; 3 patients), for the screening of mutations. BCR/ABL KD was amplified by nested PCR and sequencing was performed. Secondly, ASO-PCR was performed to confirm the results of the sequence analysis for E255K mutations...
February 2018: Oncology Letters
L L Herborg, L Nederby, H C Hasselbalch, A Aggerholm, A S Roug
INTRODUCTION: Diagnosing BCR-ABL negative myeloproliferative neoplasms (MPN) may be challenging due to overlapping features and lack of robust discriminatory parameters, especially between essential thrombocythemia (ET) and prefibrotic myelofibrosis (MF). Circulating immature hematopoietic cells are variably present in polycythemia vera (PV), ET, and MF. The C-type lectin hMICL is aberrantly expressed on hematopoietic stem cells in the majority of acute myeloid leukemia patients. However, the hMICL expression in MPN, having varying propensity of leukemic transformation, is unsettled...
February 10, 2018: International Journal of Laboratory Hematology
Gaetano Sodaro, Elena Cesaro, Giorgia Montano, Giancarlo Blasio, Federica Fiorentino, Simona Romano, Arnaud Jacquel, Patrick Aurberger, Paola Costanzo
The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression. On the other hand, Bcr-Abl positively modulates, via JAK2 activation, the expression of the c-Myc oncogene, which is required for Bcr-Abl oncogenic transformation in CML...
January 9, 2018: Oncotarget
Yue-Xing Tu, Shi-Bing Wang, Luo-Qin Fu, Shuang-Shuang Li, Qian-Peng Guo, Yi Wu, Xiao-Zhou Mou, Xiang-Min Tong
Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti-CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38-, CD34+/CD38+, and unsorted K562 cell lines using flow cytometry, western blot, RT-PCR, genomic mapping, and tumorsphere formation assays...
January 9, 2018: Oncotarget
Silvia Bono, Persio Dello Sbarba, Matteo Lulli
The introduction of BCR/Abl tyrosine kinase inhibitors (TKI), such as imatinib-mesylate (IM), has revolutioned the treatment of chronic myeloid leukemia (CML). However, although extremely effective in inducing CML remission, IM is unable to eliminate leukemia stem cells (LSC). This is largely due to the suppression of BCR/Abl protein, driven by the reduction of energy supply due to oxygen or glucose shortage, in stem cell niches of bone marrow. Here, we investigated whether, in K562 and KCL22 CML cell cultures, glucose shortage induces refractoriness of stem cell potential to IM...
January 31, 2018: Stem Cell Research
Lucie de Beauchamp, Pablo Baquero, Elodie M Kuntz, Eyal Gottlieb, G Vignir Helgason
We have recently uncovered an abnormal increase in mitochondrial oxidative metabolism in therapy-resistant chronic myeloid leukaemia stem cells (LSCs). By simultaneously disrupting mitochondrial respiration and inhibiting BCR-ABL kinase activity using the antibiotic tigecycline and imatinib respectively, we effectively eradicated LSCs and prevented disease relapse in pre-clinical animal models.
2018: Molecular & Cellular Oncology
Xiao Lin, Ruosha Li, Fangrong Yan, Tao Lu, Xuelin Huang
Optimal therapeutic decisions can be made according to disease prognosis, where the residual lifetime is extensively used because of its straightforward interpretation and formula. To predict the residual lifetime in a dynamic manner, a longitudinal biomarker that is repeatedly measured during the post-baseline follow-up period should be included. In this article, we use functional principal component analysis, a powerful and flexible tool, to handle irregularly measured longitudinal data and extract the dominant features over a specific time interval...
January 1, 2018: Statistical Methods in Medical Research
Jun Qi, Tian-Ju Wang, Li-Ping Chen, Man-Ni Wang, Jun-Hua Wu, Dan DU
OBJECTIVE: To investigate the potential relationship between the high-resolution HLA-A,-B,-DRB1 alleles and haplotype polymorphism with actute myeloid leukemia (AML) and chronic myeloid leukemia (CML) of Han people in North China. METHODS: A total of 1241 healthy unrelated Han people's bone marrow donors in North China were used as a control group, 259 patients with myeloid leukemia were genotyped at high-resolution level by means of PCR-SBT, -SSO and -SSP typing methods for HLA-A,-B,-DRB1 loci...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Dan Yu, Wei-Min Wang, Fei-Fei Wu, Ping Ma, Ling Sun, Ding-Ming Wan, Yan-Fang Liu, Xin-Sheng Xie, Chong Wang, Hui Sun
OBJECTIVE: To investigate the expression of long-chain non-coding RNA RP11-87C12.5 in acute lymphocytic leukemia and its clinical significance. METHODS: LncRNA RP11-87C12.5 expression was detected by RT-PCR in bone marrow samples from 17 control group, 33 newly diagnosed ALL patients and 26 complete remission ALL patients after chemotherapy, at the same time the clinical data were collected and the clinical significance of IncRNA RP11-87C12.5 expression was analyzed...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Yasuhiko Harada, Satoshi Nishiwaki, Takumi Sugimoto, Koichi Onodera, Tatsunori Goto, Takahiko Sato, Sonoko Kamoshita, Naomi Kawashima, Aika Seto, Shingo Okuno, Satomi Yamamoto, Toshihiro Iwasaki, Yukiyasu Ozawa, Koichi Miyamura, Yoshiki Akatsuka, Isamu Sugiura
RATIONALE: Patients with the e6a2 BCR-ABL transcript, 1 of the atypical transcripts, have been reported to have a poor prognosis, and allogeneic stem cell transplantation (ASCT) can be considered as additional therapy. However, long-term survival after ASCT for this disease is rare. PATIENT CONCERNS: This report concerns a 55-year-old female patient with e6a2 BCR-ABL-positive acute myeloid leukemia including the outcome of ASCT followed by donor lymphocyte infusion (DLI)...
December 2017: Medicine (Baltimore)
Bettina M Knoll, K Seiter
The introduction of BCR-ABL-tyrosine kinase inhibitors (TKI) for treatment of hematologic malignancies has made a significant impact on patient outcome. Contingent upon their targeted and off-target activity, therapy-associated infectious complications may occur. We present a case of cytomegalovirus pneumonitis and a case of adenovirus hemorrhagic cystitis in two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia on BCR-ABL TKI treatment and review the literature to summarize the infectious complications based on clinical data...
January 31, 2018: Infection
Ana Paula Zambuzi Cardoso Marsola, Belinda Pinto Simões, Leonardo Carvalho Palma, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Fabíola Attié de Castro
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI...
January 31, 2018: Medical Oncology
Hossein Ayatollahi, Mohammad Reza Keramati, Abbas Shirdel, Mohammad Mehdi Kooshyar, Majid Raiszadeh, Sepideh Shakeri, Mohammad Hadi Sadeghian
Background: A specific chromosomal abnormality, the Philadelphia chromosome (BCR-ABL fusion), is present in all patients with chronic myeloid leukemia (CML). The b2a2 and b3a2 fusion mRNAs encode p210 fusion protein p210 and e1a2 encode p190. The aim of this study was to evaluate the frequency of BCR-ABL fusion transcript variants in Northeast of Iranian CML patients and to compare the laboratory results of our patients. Methods: This study was conducted in 85 peripheral blood and bone marrow samples of CML patients...
2018: Caspian Journal of Internal Medicine
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