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leukemia MicroEnvironment

Mohamed Rahmani, Jewel Nkwocha, Elisa Hawkins, Xinyan Pei, Rebecca E Parker, Maciej Kmieciak, Joel D Leverson, Deepak Sampath, Andrea Ferreira-Gonzalez, Steven Grant
Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients suggesting targeting BCL-2 alone is insufficient to yield durable responses. Here we assessed the efficacy of co-administration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition...
March 20, 2018: Cancer Research
Tom Verbiest, Rosemary Finnon, Natalie Brown, Lourdes Cruz-Garcia, Paul Finnon, Grainne O'Brien, Eleanor Ross, Simon Bouffler, Cheryl L Scudamore, Christophe Badie
Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Steven M Kornblau, Peter P Ruvolo, Rui-Yu Wang, V Lokesh Battula, Elisabeth J Shpall, Vivian R Ruvolo, Teresa McQueen, YiHua Qui, Zhihong Zeng, Sherry Pierce, Rodrigo Jacamo, Suk-Young Yoo, Phuong M Le, Jeffery Sun, Numsen Hail, Marina Konopleva, Michael Andreeff
Mesenchymal stromal cells support acute myeloid leukemia cell survival in the bone marrow microenvironment. Protein expression profiles of acute myeloid leukemia-derived mesenchymal stromal cells are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from acute myeloid leukemia mesenchymal stromal cells (n = 106) with mesenchymal stromal cells from healthy donors (n = 71). Protein expression differed significantly between the two groups with nineteen proteins overexpressed in leukemia stromal cells and nine overexpressed in normal stromal cells...
March 15, 2018: Haematologica
Pingnan Xiao, Monika Dolinska, Lakshmi Sandhow, Makoto Kondo, Anne-Sofie Johansson, Thibault Bouderlique, Ying Zhao, Xidan Li, Marios Dimitriou, George Z Rassidakis, Eva Hellström-Lindberg, Nagahiro Minato, Julian Walfridsson, David T Scadden, Mikael Sigvardsson, Hong Qian
Mutations of signal-induced proliferation-associated gene 1 ( SIPA1 ), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis...
March 13, 2018: Blood Advances
Stefano Baldoni, Beatrice Del Papa, Erica Dorillo, Patrizia Aureli, Filomena De Falco, Chiara Rompietti, Daniele Sorcini, Emanuela Varasano, Debora Cecchini, Tiziana Zei, Ambra Di Tommaso, Emanuela Rosati, Gabriela Alexe, Giovanni Roti, Kimberly Stegmaier, Mauro Di Ianni, Franca Falzetti, Paolo Sportoletti
Dysregulated NOTCH1 signaling, either by gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression-based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers...
March 6, 2018: International Journal of Cancer. Journal International du Cancer
Amina M Abdul-Aziz, Manar S Shafat, Yu Sun, Christopher R Marlein, Rachel E Piddock, Stephen D Robinson, Dylan R Edwards, Zhigang Zhou, Angela Collins, Kristian M Bowles, Stuart A Rushworth
Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling...
February 28, 2018: Oncogene
Delfim Duarte, Edwin D Hawkins, Cristina Lo Celso
The interplay of cancer cells and surrounding stroma is critical in disease progression. This is particularly evident in hematological malignancies that infiltrate the bone marrow and peripheral lymphoid organs. Despite clear evidence for the existence of these interactions, the precise repercussions on the growth of leukemic cells are poorly understood. Recent development of novel imaging technology and preclinical disease models have advanced our comprehension of leukemia-microenvironment crosstalk and have potential implications for development of novel treatment options...
February 27, 2018: Blood
Mengya Si, Xiaoyang Jiao, Yazhen Li, Huanzhu Chen, Ping He, Fang Jiang
Aim: Central nervous system (CNS) metastasis is a major obstacle in the treatment of leukemia, and the underlying mechanisms of leukemia CNS metastasis are not fully understood. The present study is an investigation of the role of the CNS microenvironment in leukemia CNS metastasis. Methods: Analog blood-brain barrier (BBB) was set by coculturing human brain microvascular endothelial cells (HBMVECs) and leukemia cells (U937 and IL-60), as well as HBMVECs and sera from leukemia patients, in vitro...
2018: Cancer Management and Research
Florence Zylbersztejn, Mario Flores-Violante, Thibault Voeltzel, Franck-Emmanuel Nicolini, Sylvain Lefort, Véronique Maguer-Satta
The microenvironment (niche) governs the fate of stem cells (SC) by balancing self-renewal and differentiation. Increasing evidence indicates that the tumor niche plays an active role in cancer but its (important) properties for tumor initiation progression and resistance remain to be identified. Clinical data show that leukemic stem cells (LSC) survival is responsible for disease persistence and drug resistance probably due to their sustained interactions with the tumor niche. The Bone Morphogenetic Protein (BMP) signaling is a key pathway controlling stem cells and their niche, such as BMP2 and BMP4 important in both normal and cancer context...
February 22, 2018: Experimental Hematology
Sarah K Tasian, Martin Bornhäuser, Sergio Rutella
Abst ract: The bone marrow (BM) niche encompasses multiple cells of mesenchymal and hematopoietic origin and represents a unique microenvironment that is poised to maintain hematopoietic stem cells. In addition to its role as a primary lymphoid organ through the support of lymphoid development, the BM hosts various mature lymphoid cell types, including naïve T cells, memory T cells and plasma cells, as well as mature myeloid elements such as monocyte/macrophages and neutrophils, all of which are crucially important to control leukemia initiation and progression...
February 21, 2018: Biomedicines
Moran Gotesman, Thanh-Trang T Vo, Lee-Or Herzog, Tiffeny Tea, Sharmila Mallya, Sarah K Tasian, Marina Konopleva, David A Fruman
High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) include Philadelphia chromosome-positive (Ph+) B-ALL driven by the BCR-ABL1 oncogene and a more recently identified subtype known as BCR-ABL -like or Ph-like B-ALL. A hallmark of both Ph+ and Ph-like B-ALL is constitutive activation of tyrosine kinase signaling that is potentially targetable with tyrosine kinase inhibitors (TKIs). B-ALL cells also receive extracellular signals from the microenvironment that can maintain proliferation and survival following treatment with TKIs...
January 19, 2018: Oncotarget
Cong Wang, Yan Yang, Sujun Gao, Jingcheng Chen, Jinyuan Yu, Han Zhang, Mingxi Li, Xingying Zhan, Wei Li
Myelodysplastic syndrome (MDS) is a heterogeneous hematological malignancy, characterized by cytopenia and accompanied by a risk of transformation into acute myeloid leukemia (AML). Epidemiological studies for decades have shown association between autoimmune diseases (AIDs) and MDS. Specifically, patients with antecedent AIDs tends to have an increased risk of developing MDS, and these patients display different clinical characteristics and outcomes. Importantly, immune dysregulation has been the common driving force between MDS and AIDs pathogenesis...
February 2018: Critical Reviews in Oncology/hematology
Simar Pal Singh, Floris Dammeijer, Rudi W Hendriks
Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies...
February 19, 2018: Molecular Cancer
Gustav Arvidsson, Johan Henriksson, Birgitta Sander, Anthony P Wright
A subset of hematological cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion mediated drug resistance is an important mechanism, whereby cancer cells receive survival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture...
February 15, 2018: Haematologica
Giovanna Cutrona, Claudio Tripodo, Serena Matis, Anna Grazia Recchia, Carlotta Massucco, Marina Fabbi, Monica Colombo, Laura Emionite, Sabina Sangaletti, Alessandro Gulino, Daniele Reverberi, Rosanna Massara, Simona Boccardo, Daniela de Totero, Sandra Salvi, Michele Cilli, Mariavaleria Pellicanò, Martina Manzoni, Sonia Fabris, Irma Airoldi, Francesca Valdora, Silvano Ferrini, Massimo Gentile, Ernesto Vigna, Sabrina Bossio, Laura De Stefano, Angela Palummo, Giovanni Iaquinta, Martina Cardillo, Simonetta Zupo, Giannamaria Cerruti, Adalberto Ibatici, Antonino Neri, Franco Fais, Manlio Ferrarini, Fortunato Morabito
Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells...
February 14, 2018: Science Translational Medicine
Zhenshu Xu, Donglian Xiong, Jushun Zhang, Jingyan Zhang, Xiuli Chen, Zhizhe Chen, Rong Zhan
The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous- and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5...
February 2018: Oncology Letters
Jian Li, Wenwen Li, Kejia Huang, Yang Zhang, Gary Kupfer, Qi Zhao
Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy...
February 13, 2018: Journal of Hematology & Oncology
Parviz Kokhaei, Mohammad Hojjat-Farsangi, Fariba Mozaffari, Ali Moshfegh, Fatemeh Pak, Ali Rashidy-Pour, Marzia Palma, Lotta Hansson, Anders Österborg, Håkan Mellstedt
Crosstalk between leukemic cells and the tumor microenvironment is of importance in chronic lymphocytic leukemia (CLL). T cells seem to sustain the survival of CLL cells by various mechanisms. The Krüppel-like family of transcription factors (KLFs) are identified as regulators of proliferation and cell death. In the present study, we analyzed the expression of the wild type (WT) gene KLF6 and the oncogenic splice variant 1 (KLF6-SV1) at the mRNA level in subsets of T cells from CLL patients (n = 29), multiple myeloma patients (n = 6) and normal donors (n = 10)...
2018: PloS One
Christina Karantanou, Parimala Sonika Godavarthy, Daniela S Krause
Despite individual differences between certain leukemias, the overall survival rate in acute leukemia remains low at approximately 40%. Novel therapeutics, including targeted therapies like tyrosine kinase inhibitors, have been incorporated into treatment regimens, but most have failed at eradicating leukemic stem cells (LSCs). The causes of disease relapse, progression, and resistance to chemotherapy are as yet not entirely clear but thought to be linked to protection in the bone marrow microenvironment (BMM)...
February 12, 2018: Leukemia & Lymphoma
D S Lima, R P G Lemes, D M Matos
In tumor microenvironment, immunosuppression is a common event and results from the inhibition of activated immune cells and generation of cells with immunosuppressive capacity, as some subtypes of monocytes. The aim of this study was to evaluate the presence of immunosuppressive CD14 + /HLA-DR low/- monocytes in pediatric patients with the diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) and, moreover, verify whether the chemotherapeutic treatment has any effect on these cells. Peripheral blood (PB) and bone marrow (BM) samples were collected from 15 untreated pediatric patients...
February 10, 2018: Medical Oncology
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