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Nan Zhou, Alvaro Gutierrez-Uzquiza, Xiang Yu Zheng, Renxu Chang, Dan T Vogl, Alfred L Garfall, Luca Bernabei, Anita Saraf, Laurence Florens, Michael P Washburn, Anuradha Illendula, John H Bushweller, Luca Busino
Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs...
February 13, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kazuhiro Daino, Atsuko Ishikawa, Tomo Suga, Yoshiko Amasaki, Yotaro Kodama, Yi Shang, Shinobu Hirano-Sakairi, Mayumi Nishimura, Akifumi Nakata, Mitsuaki Yoshida, Takashi Imai, Yoshiya Shimada, Shizuko Kakinuma
Biallelic germline mutations in the DNA mismatch repair gene MLH1 lead to constitutional mismatch repair-deficiency syndrome and an increased risk for childhood hematopoietic malignancies, including lymphoma and leukemia. To examine how Mlh1 dysfunction promotes lymphoma as well as the influence of ionizing radiation (IR) exposure, we used a Mlh1-/- mouse model and whole-exome sequencing to assess genomic alterations in 23 T-cell lymphomas, including 8 spontaneous and 15 IR-associated lymphomas. Exposure to IR accelerated T-cell lymphoma induction in the Mlh1-/- mice, and whole-exome sequencing revealed that IR exposure neither increased the number of mutations nor altered the mutation spectrum of the lymphomas...
February 4, 2019: Carcinogenesis
Katharina Kriegsmann, Marc-Andrea Baertsch, Mohamed H S Awwad, Maximilian Merz, Dirk Hose, Anja Seckinger, Anna Jauch, Natalia Becker, Axel Benner, Marc S Raab, Jens Hillengass, Uta Bertsch, Jan Dürig, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Markus Munder, Katja Weisel, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial...
January 29, 2019: Blood Cancer Journal
Sung Ah Kim, Ara Go, Seung-Hyun Jo, Sun Jun Park, Young Uk Jeon, Ji Eun Kim, Heung Kyoung Lee, Chi Hoon Park, Chong-Ock Lee, Sung Goo Park, Pilho Kim, Byoung Chul Park, Sung Yun Cho, Sunhong Kim, Jae Du Ha, Jeong-Hoon Kim, Jong Yeon Hwang
Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1...
January 17, 2019: European Journal of Medicinal Chemistry
Vidyasagar Koduri, Samuel K McBrayer, Ella Liberzon, Adam C Wang, Kimberly J Briggs, Hyejin Cho, William G Kaelin
Current systems for modulating the abundance of proteins of interest in living cells are powerful tools for studying protein function but differ in terms of their complexity and ease of use. Moreover, no one system is ideal for all applications, and the best system for a given protein of interest must often be determined empirically. The thalidomide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiquitin ligase complex and alter its substrate specificity such that it targets the IKZF1 and IKZF3 lymphocyte transcription factors for destruction...
January 25, 2019: Proceedings of the National Academy of Sciences of the United States of America
Marketa Zaliova, Eliska Potuckova, Lenka Hovorkova, Alena Musilova, Lucie Winkowska, Karel Fiser, Jan Stuchly, Ester Mejstrikova, Julia Starkova, Jan Zuna, Jan Stary, Jan Trka
ERG-deletions occur recurrently in acute lymphoblastic leukemia, especially in DUX4-rearranged subtype. The ERG-deletion was shown to positively impact prognosis of patients with IKZF1-deletion and its presence precludes assignment into IKZF1plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG-deletion detection rate, evaluated ERG-deletion as a potential marker for DUX4-rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype and analyzed its clonality...
January 10, 2019: Haematologica
Ana Luiza Tardem Maciel, Caroline Pires Poubel, Elda Pereira Noronha, Maria S Pombo-de-Oliveira, Marcela Braga Mansur, Mariana Emerenciano
T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high-risk T-ALL patients. For these cases no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonises IKZF1 in T-ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T-ALL...
December 22, 2018: Genes, Chromosomes & Cancer
Salem Ali Al-Salem Bashanfer, Mohamed Saleem, Olaf Heidenreich, Emmanuel Jairaj Moses, Narazah Mohd Yusoff
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation...
December 12, 2018: Oncology Reports
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...
December 11, 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...
January 2019: 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
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