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Mati Mann, Arnav Mehta, Carl G de Boer, Monika S Kowalczyk, Kevin Lee, Pearce Haldeman, Noga Rogel, Abigail R Knecht, Daneyal Farouq, Aviv Regev, David Baltimore
Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. However, with age, the balance is disrupted, and LT-HSCs produce a myeloid-biased output, resulting in poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA sequencing (scRNA-seq), we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is prevalent among aged LT-HSCs...
December 11, 2018: Cell Reports
Claudete Esteves Klumb, Thayana da Conceição Barbosa, Gabriela Nestal de Moraes, Marcia Trindade Schramm, Mariana Emerenciano, Raquel Ciuvalschi Maia
Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR-ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6-year-old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis...
December 4, 2018: Pediatric Blood & Cancer
Jian-Feng Li, Yu-Ting Dai, Henrik Lilljebjörn, Shu-Hong Shen, Bo-Wen Cui, Ling Bai, Yuan-Fang Liu, Mao-Xiang Qian, Yasuo Kubota, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Linda Olsson, Ah Moy Tan, Hany Ariffin, Jing Chen, Junko Takita, Takahiko Yasuda, Hiroyuki Mano, Bertil Johansson, Jun J Yang, Allen Eng-Juh Yeoh, Fumihiko Hayakawa, Zhu Chen, Ching-Hon Pui, Thoas Fioretos, Sai-Juan Chen, Jin-Yan Huang
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1 -positive/ ETV6-RUNX1 -like, DUX4 fusions, ZNF384 fusions, BCR-ABL1 /Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p...
November 28, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mayumi Ueta
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC...
November 1, 2018: Investigative Ophthalmology & Visual Science
Kathryn G Roberts
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), or BCR-ABL1-like ALL, is a high-risk subtype of B-cell precursor ALL characterized by a gene expression profile similar to Ph-positive ALL, a high frequency of IKZF1 alterations, and poor outcome. The prevalence of Ph-like ALL is common among all ages, ranging from 10% to 15% in children to over 25% in young adults. Patients with Ph-like ALL harbor a diverse range of genetic alterations that activate cytokine receptor and kinase signaling and can be targeted with tyrosine kinase inhibitors...
December 2018: Best Practice & Research. Clinical Haematology
Jing Tao, Jing Yang, Guoqiang Xu
Cereblon (CRBN), a substrate receptor of the cullin-4 RING E3 ligase (CRL4), has been utilized for the targeted protein degradation via small molecular weight CRBN modulators. However, it is unclear whether and how proteins that interact with CRBN at different domains are affected by these modulators. Here, we use CRBN and its four binding partners, c-Jun, chloride channel protein CLC-1, transcription factor IKZF1, and MEIS2, as model proteins to investigate the effect of immunomodulatory drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, on their stability, ubiquitination, and interaction with CRBN...
December 9, 2018: Biochemical and Biophysical Research Communications
Quinlan L Sievers, Georg Petzold, Richard D Bunker, Aline Renneville, Mikołaj Słabicki, Brian J Liddicoat, Wassim Abdulrahman, Tarjei Mikkelsen, Benjamin L Ebert, Nicolas H Thomä
The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys2 -His2 (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface...
November 2, 2018: Science
Yohannes Gemechu, David Millrine, Shigeru Hashimoto, Jaya Prakash, Ksenia Sanchenkova, Hozaifa Metwally, Parajuli Gyanu, Sujin Kang, Tadamitsu Kishimoto
Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V ) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup...
November 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Qiuni Chen, Yuye Shi, Yue Chen, Tingting Ji, Yunjie Li, Liang Yu
Ikaros, encoded by IKZF1 (Ikaros family zinc finger 1), is an important transcription factor in the control of lymphocyte specification and differentiation. Multiple functions of Ikaros have been exerted in almost all hematopoietic cell types, from stem cells to mature lymphoid and myeloid cells. Moreover, nonhematopoietic cells are also functional targets of Ikaros. Ikaros is essential for normal hematopoiesis, autoimmune and tumor suppression. Ikaros mutations were associated with lymphoblastic cells deficiency, autoimmunity and malignancies development, including hematological malignancies (leukemia) and solid tumors...
October 22, 2018: Gene
Dennis Liang Fei, Tao Zhen, Benjamin Durham, John Ferrarone, Tuo Zhang, Lisa Garrett, Akihide Yoshimi, Omar Abdel-Wahab, Robert K Bradley, Paul Liu, Harold Varmus
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of U2af1 (S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development...
October 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jing Zheng, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, Cristina Gasparetto, Nelson Chao, Allen Ebens, Jianda Hu, Yubin Kang
Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities...
October 9, 2018: Cancer Letters
Jing-Jing Xu, Hui-Xia Xiong
Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of precursor B-cell acute lymphoblastic leukemia (BCP-ALL) with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL, which is a clinically and biologically heterogeneous subtype of BCP-ALL. The prognosis correlats negatively with age increasing. The incidence of this "Ph-like" subtype may be higher in young adults. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor genes and kinase signaling pathways...
October 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Mohamed H S Awwad, Katharina Kriegsmann, Julian Plaumann, Michael Benn, Jens Hillengass, Marc S Raab, Uta Bertsch, Markus Munder, Katja Weisel, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Jan Dürig, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Purpose : While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. Experimental design : We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value...
2018: Oncoimmunology
Christine I Chen, Harminder Paul, Susi Snitzler, Sumeet Kakar, Lisa W Le, Ellen N Wei, Anthea Lau, James B Johnston, Spencer B Gibson, Michelle Queau, David Spaner, Danielle Croucher, Barbara Sherry, Suzanne Trudel
Lenalidomide has anti-tumor activity in CLL but can be complicated by tumor lysis syndrome (TLS) and tumor flare (TF). In our previous study using low-dose lenalidomide in treatment-naive CLL, TLS was averted but TF remained frequent and complete responses (CR) were rare, despite treatment to progression. The addition of dexamethasone may mitigate TF and enable lenalidomide dose escalation, achieving durable response without long-term use. In this phase 2 trial, 31 treatment-naive CLL patients received lenalidomide (target 25mg daily) plus dexamethasone for a finite 18 cycles...
October 2, 2018: Leukemia & Lymphoma
Gang Lu, Stephanie Weng, Mary Matyskiela, Xinde Zheng, Wei Fang, Scott Wood, Christine Surka, Reina Mizukoshi, Chin-Chun Lu, Derek Mendy, In Sock Jang, Kai Wang, Mathieu Marella, Suzana Couto, Brian Cathers, James Carmichael, Philip Chamberlain, Mark Rolfe
The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN ) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism...
September 20, 2018: ELife
Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David C S Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis...
September 18, 2018: Blood
Yi Zhang, Fei Yang
Osteosarcoma is the most common type of primary malignant bone tumor observed in children and adolescents. The aim of the present study was to identify an osteosarcoma-related gene module (OSM) by looking for a dense module following the integration of signals from genome-wide association studies (GWAS) into the human protein-protein interaction (PPI) network. A dataset of somatic mutations in osteosarcoma was obtained from the dbGaP database and their testing P-values were incorporated into the PPI network from a recent study using the dmGWAS bioconductor package...
September 2018: Experimental and Therapeutic Medicine
Anna Lucia Fedullo, Monica Messina, Loredana Elia, Alfonso Piciocchi, Valentina Gianfelici, Alessia Lauretti, Stefano Soddu, Maria Cristina Puzzolo, Clara Minotti, Felicetto Ferrara, Bruno Martino, Patrizia Chiusolo, Valeria Calafiore, Stefania Paolini, Marco Vignetti, Antonella Vitale, Anna Guarini, Robin Foà, Sabina Chiaretti
To shed light into the molecular basis of Ph+ acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult Ph+ acute lymphoblastic leukemia patients enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that Ph+ acute lymphoblastic leukemia patients carry 7.8 lesions/case on average, with deletions outnumbering gains (88% vs 12%)...
September 6, 2018: Haematologica
Yusuke Furukawa, Yoshiaki Kuroda, Jiro Kikuchi
Multiple myeloma (MM) cells acquire dormancy and drug resistance via their interaction with bone marrow stroma cells (BMSCs) in a hypoxic microenvironment. In this study, we found a positive expression of CD180/MD-1 complex (a non-canonical toll-like receptor) on MM cells, which was markedly up-regulated under adherent and/or hypoxic conditions. Bacterial lipopolysaccharide (LPS) enhanced the growth of MM cells via the activation of MAP kinases, an effect which showed a positive correlation with the expression levels of CD180...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Christian Steinebach, Stefanie Lindner, Namrata D Udeshi, Deepak C Mani, Hannes Kehm, Simon Köpff, Steven A Carr, Michael Gütschow, Jan Krönke
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation...
September 21, 2018: ACS Chemical Biology
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