Chiu, SK, Orive, SL, Moon, MJ, Saw, J, Ellis, S, Kile, BT, Huang, Y, Chacon, D, Pimanda, JE, Beck, D, Hamilton, JR, Tremblay, CS & Curtis, DJ 2019, 'Shared roles for Scl and Lyl1 in murine platelet production and function', Blood, vol. 134, no. 10, pp. 826-835.View/Download from: Publisher's site
© 2019 by The American Society of Hematology. The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.
Beck, D, Thoms, JAI, Palu, C, Herold, T, Shah, A, Olivier, J, Boelen, L, Huang, Y, Chacon, D, Brown, A, Babic, M, Hahn, C, Perugini, M, Zhou, X, Huntly, BJ, Schwarzer, A, Klusmann, J-H, Berdel, WE, Wörmann, B, Büchner, T, Hiddemann, W, Bohlander, SK, To, LB, Scott, HS, Lewis, ID, D'Andrea, RJ, Wong, JWH & Pimanda, JE 2018, 'A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients.', Leukemia, vol. 32, no. 2, pp. 263-272.View/Download from: UTS OPUS or Publisher's site
Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.
Chiu, SK, Saw, J, Huang, Y, Sonderegger, SE, Wong, NC, Powell, DR, Beck, D, Pimanda, JE, Tremblay, CS & Curtis, DJ 2018, 'A novel role for Lyl1 in primitive erythropoiesis', DEVELOPMENT, vol. 145, no. 19.View/Download from: UTS OPUS or Publisher's site
Jing, D, Huang, Y, Liu, X, Sia, KCS, Zhang, JC, Tai, X, Wang, M, Toscan, CE, McCalmont, H, Evans, K, Mayoh, C, Poulos, RC, Span, M, Mi, J, Zhang, C, Wong, JWH, Beck, D, Pimanda, JE & Lock, RB 2018, 'Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia', CANCER CELL, vol. 34, no. 6, pp. 906-+.View/Download from: UTS OPUS or Publisher's site
Liu, Q, Thoms, JAI, Nunez, AC, Huang, Y, Knezevic, K, Packham, D, Poulos, RC, Williams, R, Beck, D, Hawkins, NJ, Ward, RL, Wong, JWH, Hesson, LB, Sloane, MA & Pimanda, JE 2018, 'Disruption of a-35 kb Enhancer Impairs CTCF Binding and MLH1 Expression in Colorectal Cells', CLINICAL CANCER RESEARCH, vol. 24, no. 18, pp. 4602-4611.View/Download from: UTS OPUS or Publisher's site
Schwarzer, A, Emmrich, S, Schmidt, F, Beck, D, Ng, M, Reimer, C, Adams, FF, Grasedieck, S, Witte, D, Käbler, S, Wong, JWH, Shah, A, Huang, Y, Jammal, R, Maroz, A, Jongen-Lavrencic, M, Schambach, A, Kuchenbauer, F, Pimanda, JE, Reinhardt, D, Heckl, D & Klusmann, J-H 2017, 'The non-coding RNA landscape of human hematopoiesis and leukemia.', Nature Communications, vol. 8, no. 1, pp. 1-17.View/Download from: UTS OPUS or Publisher's site
Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.
Unnikrishnan, A, Papaemmanuil, E, Beck, D, Deshpande, NP, Verma, A, Kumari, A, Woll, PS, Richards, LA, Knezevic, K, Chandrakanthan, V, Thoms, JAI, Tursky, ML, Huang, Y, Ali, Z, Olivier, J, Galbraith, S, Kulasekararaj, AG, Tobiasson, M, Karimi, M, Pellagatti, A, Wilson, SR, Lindeman, R, Young, B, Ramakrishna, R, Arthur, C, Stark, R, Crispin, P, Curnow, J, Warburton, P, Roncolato, F, Boultwood, J, Lynch, K, Jacobsen, SEW, Mufti, GJ, Hellstrom-Lindberg, E, Wilkins, MR, MacKenzie, KL, Wong, JWH, Campbell, PJ & Pimanda, JE 2017, 'Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.', Cell Reports, vol. 20, no. 3, pp. 572-585.View/Download from: UTS OPUS or Publisher's site
Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.
Thoms, JAI, Knezevic, K, Liu, JJ, Glaros, EN, Thai, T, Qiao, Q, Campbell, H, Packham, D, Huang, Y, Papathanasiou, P, Tunningley, R, Whittle, B, Yeung, AWS, Chandrakanthan, V, Hesson, L, Chen, V, Wong, JWH, Purton, LE, Ward, RL, Thomas, SR & Pimanda, JE 2016, 'Arrested Hematopoiesis and Vascular Relaxation Defects in Mice with a Mutation in Dhfr', MOLECULAR AND CELLULAR BIOLOGY, vol. 36, no. 8, pp. 1222-1236.View/Download from: UTS OPUS or Publisher's site
Huang, Y, Thoms, JAI, Tursky, ML, Knezevic, K, Beck, D, Chandrakanthan, V, Suryani, S, Olivier, J, Boulton, A, Glaros, EN, Thomas, SR, Lock, RB, MacKenzie, KL, Bushweller, JH, Wong, JWH & Pimanda, JE 2016, 'MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation', LEUKEMIA, vol. 30, no. 7, pp. 1552-1561.View/Download from: UTS OPUS or Publisher's site
Unnikrishnan, A, Guan, YF, Huang, Y, Beck, D, Thoms, JAI, Peirs, S, Knezevic, K, Ma, S, de Walle, IV, de Jong, I, Ali, Z, Zhong, L, Raftery, MJ, Taghon, T, Larsson, J, MacKenzie, KL, Van Vlierberghe, P, Wong, JWH & Pimanda, JE 2016, 'A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network.', Nucleic Acids Research, vol. 44, no. 22, pp. 10644-10661.View/Download from: UTS OPUS or Publisher's site
Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.
Tursky, ML, Beck, D, Thoms, JAI, Huang, Y, Kumari, A, Unnikrishnan, A, Knezevic, K, Evans, K, Richards, LA, Lee, E, Morris, J, Goldberg, L, Izraeli, S, Wong, JWH, Olivier, J, Lock, RB, MacKenzie, KL & Pimanda, JE 2015, 'Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias', LEUKEMIA, vol. 29, no. 4, pp. 819-827.View/Download from: UTS OPUS or Publisher's site
Wong, JJ-L, Ritchie, W, Ebner, OA, Selbach, M, Wong, JWH, Huang, Y, Gao, D, Pinello, N, Gonzalez, M, Baidya, K, Thoeng, A, Khoo, T-L, Bailey, CG, Holst, J & Rasko, JEJ 2013, 'Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation', CELL, vol. 154, no. 3, pp. 583-595.View/Download from: UTS OPUS or Publisher's site
Jing, D, Huang, Y, Liu, X, Sia, K, Poulos, RC, Span, M, Zhang, C, Mi, J, Wong, JWH, Beck, D, Pimanda, JE & Lock, RB 2018, 'Lymphocyte-specific chromatin accessibility predetermines glucocorticoid resistance in acute lymphoblastic leukemia', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, Chicago, IL.View/Download from: Publisher's site
Beck, D, Thoms, J, Palu, C, Herold, T, Shah, A, Olivier, J, Boelen, L, Huang, Y, Chacon, D, Brown, A, Babic, M, Hahn, C, Perugini, M, Zhou, X, Huntly, B, Berdel, W, Woermann, B, Buechner, T, Hiddemann, W, Bohlander, S, Scott, H, Lewis, I, D'Andrea, R, Wong, J & Pimanda, J 2016, 'Integrative analysis of lincrna expression in 922 acute myeloid leukemia patients reveals multiple prognostic gene signatures', Haematologica, pp. 208-209.