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Chonghua Yao, Michihiro Kobayashi, Sisi Chen, Sarah C Nabinger, Rui Gao, Stephen Z Liu, Takashi Asai, Yan Liu
Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear...
October 20, 2017: Oncotarget
Kostandin V Pajcini, Lanwei Xu, Lijian Shao, Jelena Petrovic, Karol Palasiewicz, Yumi Ohtani, Will Bailis, Curtis Lee, Gerald B Wertheim, Rajeswaran Mani, Natarajan Musuthamy, Yunlei Li, Jules P P Meijerink, Stephen C Blacklow, Robert B Faryabi, Sara Cherry, Warren S Pear
Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex...
November 14, 2017: Science Signaling
Cristina Prieto, Rolf Marschalek, Alessa Kühn, Adelheid Bursen, Clara Bueno, Pablo Menéndez
The translocation t(4;11)(q21;q23) is the hallmark genetic abnormality associated with infant pro-B acute lymphoblastic leukemia (B-ALL) and has the highest frequency of rearrangement in Mixed-lineage leukemia (MLL) leukemias. Unlike other MLL translocations, MLL-AF4-induced proB-ALL is exceptionally difficult to model in mice/humans. Previous work has investigated the relevance of the reciprocal translocation fusion protein AF4-MLL for t(4;11) leukemia, finding that AF4-MLL is capable of inducing proB-ALL without requirement for MLL-AF4 when expressed in murine hematopoietic stem/progenitor cells (HSPCs)...
October 10, 2017: Oncotarget
Katharina Schönberger, Nina Cabezas-Wallscheid
Metabolic cues and (epi-)genetic factors are emerging regulators of hematopoietic stem cell (HSC) potency. Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, show that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity.
November 2, 2017: Cell Stem Cell
Yang-Feng Wang, Li-Qun Wu, Yi-Ni Liu, Yong-Yi Bi, Hong Wang
OBJECTIVE: An increasing amount of evidence shows that childhood leukemia is initiated in utero. Birth characteristics initiated in utero, such as gestational age, may play a role in leukemogenesis. The purpose of our meta-analysis is to explore the association between gestational age and childhood leukemia. METHODS: Relevant studies up to 21 April 2017 were collected by searching PubMed and EMBASE databases. Subgroup analysis, sensitivity analysis and publication bias assessment were conducted...
November 3, 2017: Hematology (Amsterdam, Netherlands)
Marlise R Luskin, Daniel J DeAngelo
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with inadequate treatment options. Approximately one-third of cases have a FLT3-ITD or FLT3-TKD mutation which leads to constitutive tyrosine kinase activation which contributes to leukemogenesis. The FLT3-ITD mutation is associated with a particularly poor prognosis. Midostaurin is a multi-kinase inhibitor active against the FLT3 receptor. Midostaurin was approved by the US FDA in April 2017 for treatment of newly diagnosed FLT3-mutant AML in combination with chemotherapy...
October 30, 2017: Expert Review of Hematology
Sze-Hwei Lee, Yu-Chiao Chiu, Yi-Hung Li, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien
DOCK family genes encode evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase involving multiple biological functions. Yet the patterns and prognostic significance of their expression in acute myeloid leukemia (AML) remain unexplored. Here we analyzed the expression patterns of 11 DOCK family genes in AML cells based on the array data of 347 patients from our cohort and several other published datasets. We further focused on the implications of the expression of DOCK1 since it was the only one in DOCK family to be associated with survival...
September 22, 2017: Oncotarget
A Gupta, L Kumar
Cytogenetic anomalies involving the 3q26 chromosomal region are rare in acute myeloid leukemia (AML). There is no such description of these anomalies from the Indian sub-continent. A total of 174 AML patients were admitted to our hospital for therapy between January 2001 and January 2008. Cytogenetic studies could be done in 115 patients; which revealed three cases with 3q26 anomalies. All were males. In the first two cases, the anomaly was detected in all the metaphases. The common features seen were the presence of only mild thrombocytopenia (relatively high platelet counts when assessed against the background of AML with high blast percentages), monosomy 7, myeloperoxidase positive blasts, mild eosinophilia, and poor therapeutic response...
October 23, 2017: Journal of Postgraduate Medicine
Jianbiao Zhou, Xiao Lu, Tuan Zea Tan, Wee-Joo Chng
Acute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5-year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X-Linked Inhibitor of Apoptosis (XIAP), one of the inhibitor of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (abbreviation: RO-BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML...
October 24, 2017: Molecular Oncology
Matthew J Smith, Elizabeth Ottoni, Noboru Ishiyama, Marilyn Goudreault, André Haman, Claus Meyer, Monika Tucholska, Genevieve Gasmi-Seabrook, Serena Menezes, Rob C Laister, Mark D Minden, Rolf Marschalek, Anne-Claude Gingras, Trang Hoang, Mitsuhiko Ikura
Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization...
October 23, 2017: Nature Communications
Chi-Ping Chan, Kin-Hang Kok, Dong-Yan Jin
Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus discovered to cause adult T-cell leukemia (ATL), a highly aggressive blood cancer. HTLV-1 research in the past 35 years has been most revealing in the mechanisms of viral oncogenesis. HTLV-1 establishes a lifelong persistent infection in CD4(+) T lymphocytes. The infection outcome is governed by host immunity. ATL develops in 2-5% of infected individuals 30-50 years after initial exposure. HTLV-1 encodes two oncoproteins Tax and HBZ, which are required for initiation of cellular transformation and maintenance of cell proliferation, respectively...
2017: Advances in Experimental Medicine and Biology
Sebastian Nieke, Nighat Yasmin, Kiyokazu Kakugawa, Tomomasa Yokomizo, Sawako Muroi, Ichiro Taniuchi
BACKGROUND: The Runt-related transcription factors (Runx) are a family of evolutionarily conserved transcriptional regulators that play multiple roles in the developmental control of various cell types. Among the three mammalian Runx proteins, Runx1 is essential for definitive hematopoiesis and its dysfunction leads to human leukemogenesis. There are two promoters, distal (P1) and proximal (P2), in the Runx1 gene, which produce two Runx1 isoforms with distinct N-terminal amino acid sequences, P1-Runx1 and P2-Runx1...
October 18, 2017: BMC Developmental Biology
James N Cooper, Neal S Young
Clonal hematopoiesis occurs normally, especially with aging, and in the setting of disease, not only myeloid cancers but in bone marrow failure. In cancer, malignant clones are characterized by recurrent somatic mutations in specific sets of genes, but the direct relationship of such mutations to leukemogenesis, when they occur in an apparently healthy older individual or after recovery from immune aplastic anemia, is uncertain. Here we emphasize a view of clonal evolution that stresses natural selection over deterministic ontogeny, and we stress the selective role of the marrow's, and organism's, environment...
October 18, 2017: Blood
Geórgia Muccillo Dexheimer, Jayse Alves, Laura Reckziegel, Gabrielle Lazzaretti, Ana Lucia Abujamra
During the onset and progression of hematological malignancies, many changes occur in cellular epigenome, such as hypo- or hypermethylation of CpG islands in promoter regions. DNA methylation is an epigenetic modification that regulates gene expression and is a key event for tumorigenesis. The continuous search for biomarkers that signal early disease, indicate prognosis, and act as therapeutic targets has led to studies investigating the role of DNA in cancer onset and progression. This review focuses on DNA methylation changes as potential biomarkers for diagnosis, prognosis, response to treatment, and early toxicity in acute myeloid leukemia and myelodysplastic syndrome...
2017: Disease Markers
Ke Zhu, Benchun Jiang, Ying Yang, Rong Hu, Zhuogang Liu
DACT1 has been shown to participate in the development of many types of tumors; however, its role and precise molecular mechanisms in leukemia are unclear. In this study, we investigated the effect of DACT1 on KG-1α leukemia cells to further understand the mechanisms of DACT1-mediated tumor suppression. We transfected a DACT1 expression plasmid to upregulate DACT1 in KG-1α cells and analyzed the resulting phenotypic changes. The results demonstrated that DACT1 overexpression inhibited KG-1α proliferation, increased apoptosis, and arrested cells in the G0/G1 phase...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Zachary Fischer, Rahul Das, Anna Shipman, Jin-Yuan Fan, Laramie Pence, Samuel Bouyain, Leonard L Dobens
Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to Akt kinase to block its phosphorylation-activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human Trib3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding resulting in reduced Akt phosphorylation and is associated with a predisposition to Type II diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis...
October 12, 2017: Disease Models & Mechanisms
Tao Zhen, Erika Kwon, Ling Zhao, Jingmei Hsu, R Katherine Hyde, Ying Lu, Lemlem Alemu, Nancy A Speck, P Paul Liu
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFβ-SMMHC (encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain-helicase-DNA binding protein 7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells...
October 10, 2017: Blood
(no author information available yet)
METTL3 is upregulated in acute myeloid leukemia compared with other tumors and normal HSPCs.
November 2017: Cancer Discovery
Toshihiro Miyamoto, Yoshikane Kikushige, And Goichi Yoshimoto
Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Keiyo Takubo, Takayuki Morikawa, Hiroshi Kobayashi
During steady-state conditions, hematopoietic stem cells (HSCs) maintain a quiescent status in the cell cycle. Upon infection or inflammation, bone marrow HSCs begin proliferating and generating differentiated hematopoietic cells via multi-lineage differentiation and self-renewal; this effect is partially due to the alteration of their surrounding microenvironment or niche. In addition, recent studies have revealed that the bone marrow niche critically contributes to abnormal hematopoiesis, including leukemogenesis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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