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Genetics on leukemia

Yufei Chen, Kenneth L Jones, Konstantinos Anastassiadis, Andrea Kranz, A Francis Stewart, Jolanta Grembecka, Matthew Meyerson, Patricia Ernst
Disrupting protein-protein interaction for molecularly targeted cancer therapeutics can be a challenging but promising strategy. Compounds that disrupt the interaction between Menin, a chromatin-binding protein, and oncogenic MLL fusion proteins (FPs) have shown significant promise in pre-clinical models of leukemia and show a high degree of selectivity for leukemia versus normal hematopoietic cells. Biochemical and structural studies demonstrate that, in addition to disrupting Menin-MLL-FP interaction, such compounds also inhibit Menin-MLL1, Menin-MLL2, and other Menin interacting proteins...
October 10, 2018: Experimental Hematology
Valeria Buccheri, Wolney Gois Barreto, Laura Maria Fogliatto, Marcelo Capra, Mariana Marchiani, Vanderson Rocha
Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance...
October 12, 2018: Annals of Hematology
Sanam Loghavi, Joseph D Khoury
PURPOSE OF REVIEW: The goal of this review is to provide a practical and comprehensive update on changes in the classification of chronic myelomonocytic leukemia (CMML) and a summary of the most recent developments in our understanding of its genomic landscape, prognostic models, and therapeutic approaches. RECENT FINDINGS: The 2017 revision of the World Health Organization (WHO) classification includes substantial changes to the subclassification CMML. The clinical utility of the newly revised subclassification scheme is discussed...
October 11, 2018: Current Hematologic Malignancy Reports
Maura C O'Leary, Xiaobin Lu, Ying Huang, Xue Lin, Iftekhar Mahmood, Donna Przepiorka, Denise Gavin, Shiowjen Lee, Ke Liu, Bindu George, Wilson Bryan, Marc R Theoret, Richard Pazdur
Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals, East Hanover, NJ) is a CD19-directed genetically-modified autologous T-cell immunotherapy. On August 30, 2017, the U.S. Food and Drug Administration approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR and minimal residual disease (MRD) < 0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202)...
October 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
King Pan Ng, Aditi Manjeri, Lin Ming Lee, Zhu En Chan, Chin Yee Tan, Qiancheng Darren Tan, A'Qilah Majeed, Kian Leong Lee, Charles Chuah, Toshio Suda, S Tiong Ong
Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist in hosts and evade therapy. Accordingly, there is significant interest in drugging cancer-specific hypoxic responses. However, a major challenge in leukemia is identifying differential and druggable hypoxic responses between leukemic and normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of the urea cycle, is overexpressed in CML but not normal progenitors. ARG2 is a target of the hypoxia inducible factors (HIF1-α and HIF2-α), and is required for the generation of polyamines which are required for cell growth...
2018: PloS One
Hiroshi Moritake
Recently, the modern technique of comprehensive genomic analysis has identified both somatic mutations originating from tumor cells and germline mutations as causative genes of inherited familial leukemias among which Fanconi anemia and Li-Fraumeni syndrome are well known. Pathogenic germline mutations occur in various pathways, affecting DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, neutrophil development, and other critical cellular processes. The clinical manifestations of germline mutations present a wide phenotypic spectrum of patients displaying congenital anomalies, early-onset myelodysplastic syndrome, or no medical problems until the developing leukemia...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Motohiro Kato
Molecular genomic studies for acute lymphoblastic leukemia (ALL) have been focused on genetic alterations in leukemic cells, while germline cells are mainly used as a control to identify the somatic mutation. However, recent studies demonstrate that germline mutations may contribute to the pathogenesis of ALL, and currently, the genetic background has been found to play an essential role in the development of pediatric ALL. An association between polymorphism and adverse events has already been reported, and recent genomic analyses of familial ALL cases identified inherited causative genes for ALL...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Yasunori Kogure, Keisuke Kataoka
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. This disease is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. Not only viral proteins, such as Tax and HBZ, but also additional genetic and epigenetic aberrations, including gain-of-function alterations in the components of T-cell receptor/NF-κB pathway or deteriorating alterations responsible for immune surveillance, are essential for ATL development and progression. Furthermore, recent investigation has demonstrated the effects of genetic and epigenetic alterations prevalently identified in ATL on the disease phenotype and its clinical outcomes...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Tetsuzo Tauchi
Fatal events during treatment with ABL tyrosine kinase inhibitors (ABL TKIs) have been reported, and there have been concerns of high mortality rate in patients with chronic myeloid leukemia receiving ABL TKIs. The predictive factors of patients treated with ABL TKIs who are at risk of potentially fatal toxicities remain unknown. Although this scenario appears discouraging, the risk of severe toxicity might be predicted by investigating the effect of genetic variation on the disposition of ABL TKIs. Global genomic surveys should be conducted to identify factors contributing to an increased risk of toxicity using multivariable analyses with particular reference to ABL TKIs pharmacokinetics and baseline clinical characteristics...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Yuichi Ishikawa
Core binding factor-acute myeloid leukemia (CBF-AML) comprises AML with t (8;21) (p22;q22) and inv16 (q16q16) /t (16;16) (q16;q16) and accounts for 20% of AML cases. The 2016 WHO classification categorized CBF-AML under AML with recurrent genetic abnormalities and considered it as a favorable risk group with a higher remission rate and better overall survival with high-dose cytarabine post-remission therapy. However, relapse occurs in approximately 40% of patients, thereby necessitating the establishment of risk stratification and risk-adapted therapy in CBF-AML...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Valeria Tosello, Gloria Milani, Annalisa Martines, Nadia Macri, Wouder Van Loocke, Filip Matthijssens, Barbara Buldini, Sonia Minuzzo, Deborah Bongiovanni, Richard Fabian Schumacher, Alberto Amadori, Pieter Van Vlierberghe, Erich Piovan
MYC -translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC -translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis...
October 9, 2018: Cells
Asma Bibi, Shrutika Java, Shruti Chaudhary, Swapnali Joshi, Russel Mascerhenas, Nikhil Rabade, Prashant Tembhare, Papagudi Ganesan Subramanian, Sumeet Gujral, Hari Menon, Navin Khattry, Manju Sengar, Bhausaheb Bagal, Hasmukh Jain, Nikhil Patkar
Background: BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes. Aims: To determine the prevalence of BRAFV600E in HCL from our center and derive clinicopathological correlation, if any. Materials and Methods: A 9-year retrospective analysis of 46 consecutive cases of HCL diagnosed on morphology and immunophenotyping was done. Stained smears were used as samples for amplification refractory mutation system polymerase-chain reaction using fluorescent primers for mutation detection...
October 2018: Indian Journal of Pathology & Microbiology
Elie El Rassy, Alain Chebly, Rima Korban, Warde Semaan, Ziad Bakouny, Tarek Assi, Hampig Raphael Kourie, Fadi El Karak, Eliane Chouery, Joseph Kattan
Aim: We aimed to understand the biology of chronic lymphocytic leukemia (CLL) patients in Lebanon. Materials & methods: We applied conventional cytogenetic and FISH studies on Lebanese patients diagnosed with CLL and undergoing a watch and wait approach. Results: Our study disclosed 53.6% of patients with aberrant karyotypes among which 26.7% were complex karyotypes. Genetic aberrations included del(13q14) 46.4%, 14q32 translocation in 25%, trisomy 12 in 14...
December 2017: International Journal of Hematologic Oncology
Yang Jiao
OBJECTIVE: To explore clinical features of patients with de novo primary acute myeloid leukemia (AML) and various chromosomal karyotypes. METHODS: Clinical data of 144 patients was retrospectively reviewed. The patients included 76 males and 68 females, with a median age of 41.5 years and inter-quartile ranging from 25.25 to 53.75 years. Based on cytogenetic prognostic stratification criteria, the patients were divided into good prognosis (GP group, 55 cases), moderate prognosis (MP group, 71 cases) and poor prognosis (PP group, 18 cases)...
October 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Fei Yan, Aref Al-Kali, Zijie Zhang, Jun Liu, Jiuxia Pang, Na Zhao, Chuan He, Mark R Litzow, Shujun Liu
N6 -methyladenosine (m6 A) on mRNAs is critical for various biological processes, yet whether m6 A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on m6 A reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-m6 A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m6 A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice...
October 8, 2018: Cell Research
Xian-Bo Huang, Chun-Mei Yang, Qing-Mei Han, Xiu-Jin Ye, Wen Lei, Wen-Bin Qian
Although the treatment of adult T-cell acute lymphoblastic leukemia (T-ALL) has been significantly improved, the heterogeneous genetic landscape of the disease often causes relapse. Aberrant activation of mammalian target of rapamycin (mTOR) pathway in T-ALL is responsible for treatment failure and relapse, suggesting that mTOR inhibition may represents a new therapeutic strategy. In this study, we investigated whether the mTOR complex 1 (mTORC1) inhibitor everolimus could be used as a therapeutic agent against human T-ALL...
October 8, 2018: Acta Pharmacologica Sinica
Rosa Pennisi, Jacopo Albanesi, Paolo Ascenzi, Clara Nervi, Alessandra di Masi
Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the expansion of hematopoietic stem/progenitor cells (HPCs) blocked at different stages of maturation/differentiation. The poor outcome of AMLs necessitates therapeutic improvement. In AML, genes encoding for myeloid transcription factors, signaling receptors regulating cell proliferation, and epigenetic modifiers can be mutated by somatically acquired genetic mutations or altered by chromosomal translocations. These mutations modify chromatin organization at genes sites regulating HPCs proliferation, terminal differentiation, and DNA repair, contributing to the development and progression of the disease...
October 8, 2018: IUBMB Life
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
Rabea Wagener, Cristina López, Kortine Kleinheinz, Julia Bausinger, Sietse M Aukema, Inga Nagel, Umut H Toprak, Julian Seufert, Janine Altmüller, Holger Thiele, Christof Schneider, Julia Kolarova, Jeongbin Park, Daniel Hübschmann, Eva M Murga Penas, Hans G Drexler, Andishe Attarbaschi, Randi Hovland, Eigil Kjeldsen, Michael Kneba, Udo Kontny, Laurence de Leval, Peter Nürnberg, Ilske Oschlies, David Oscier, Brigitte Schlegelberger, Stephan Stilgenbauer, Wilhelm Wössmann, Matthias Schlesner, Birgit Burkhardt, Wolfram Klapper, Elaine S Jaffe, Ralf Küppers, Reiner Siebert
The "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue" notes instances of Burkitt lymphoma/leukemia (BL) with IG- MYC -rearrangement displaying a B-cell precursor immunophenotype (termed herein "preBLL"). To characterize the molecular pathogenesis of preBLL we investigated 13 preBLL cases (including one cell line) of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA-methylation profiling. In five patients with reads across the IG- MYC breakpoint junctions we found evidence that the translocation derived from an aberrant VDJ-recombination, as typical for IG translocations arising in B-cell precursors...
October 3, 2018: Blood
Ting-Chi Yeh, Der-Cherng Liang, Hsi-Che Liu, Tang-Her Jaing, Shih-Hsiang Chen, Jen-Yin Hou, Chao-Ping Yang, Ying-Jung Huang, Hsien-Wen Yao, Ting-Yu Huang, Tung-Huei Lin, Lee-Yung Shih
BACKGROUND: The leukemogenesis of T-cell acute lymphoblastic leukemia (T-ALL) involves multistep processes of genetic alterations. We aimed to determine the genetic alterations including common fusion transcripts, overexpression of T-cell transcription factor oncogenes, and deletion or mutation of targeted genes in pediatric T-ALL in Taiwan as well as their impact on outcomes in those treated with the Taiwan Pediatric Oncology Group-ALL-2002 protocol. PROCEDURE: Between 1995 and 2015, bone marrow samples obtained from 102 children aged <18 years consecutively diagnosed with T-ALL were examined...
October 2, 2018: Pediatric Blood & Cancer
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