Article
Oncology
Wenxiang Sun, Jingtao Guo, David McClellan, Alexandra Poeschla, Diana Bareyan, Mattie J. Casey, Bradley R. Cairns, Dean Tantin, Michael E. Engel
Summary: GFI1 and IKAROS cooperate to regulate the expression of hallmark T-cell development genes in T-acute lymphoblastic leukemia (ALL) cells. NOTCH3, a key factor in T-ALL pathogenesis, is transactivated by GFI1 and IKAROS. The SNAG domain of GFI1 plays an important role in this process.
MOLECULAR CANCER RESEARCH
(2022)
Article
Oncology
Mithun Vinod Shah, Elizabeth Ngoc Hoa Tran, Syed Shah, Rakchha Chhetri, Anmol Baranwal, Dariusz Ladon, Carl Shultz, Aref Al-Kali, Anna L. Brown, Dong Chen, Hamish S. Scott, Patricia Greipp, Daniel Thomas, Hassan B. Alkhateeb, Deepak Singhal, Naseema Gangat, Sharad Kumar, Mrinal M. Patnaik, Christopher N. Hahn, Chung Hoow Kok, Ayalew Tefferi, Devendra K. Hiwase
Summary: Revised diagnostic criteria for myeloid neoplasms recommended major changes regarding TP53(mut) MN, but these changes have not been specifically examined in therapy-related myeloid neoplasm (t-MN). In this study, TP53(mut) was analyzed in 488 t-MN patients and significant findings were observed. TP53(mut) t-MN with a variant allele frequency (VAF) >= 10% had distinct clinical and biological characteristics and significantly shorter survival compared to TP53(wt) cases.
BLOOD CANCER JOURNAL
(2023)
Article
Oncology
Xian Chen, Chuchu Tian, Zhuanghui Hao, Lingang Pan, Minglin Hong, Wei Wei, Daniel Muteb Muyey, Hongwei Wang, Xiuhua Chen
Summary: In this study, we investigated the biological and prognostic significance of DNMT3A mutations in acute myeloid leukemia (AML) by analyzing 171 adult patients with de novo cytogenetically normal AML. DNMT3A(High) patients with a variant allele frequency (VAF) above 42% showed higher white blood cell count, higher lactate dehydrogenase level, lower complete remission rate, and shorter overall survival compared to DNMT3A(Low) patients. We also identified two different comutated genotypes, DNMT3A(mut)NPM1(mut)FLT3-ITDmut and DNMT3A(mut)IDH1/IDH2(mut), which showed different clinical outcomes. Multivariate analyses revealed that DNMT3A(High) and DNMT3A(mut)NPM1(mut)FLT3-ITDmut were independently associated with lower complete remission rate and shorter overall survival and relapse-free survival, respectively.
Article
Multidisciplinary Sciences
Sarah Ennis, Alessandra Conforte, Eimear O'Reilly, Javid Sabour Takanlu, Tatiana Cichocka, Sukhraj Pal Dhami, Pamela Nicholson, Philippe Krebs, Pilib O. Broin, Eva Szegezdi
Summary: In this study, a single-cell gene expression database of 339,381 bone marrow cells was established to comprehensively characterize the microenvironment of both healthy and acute myeloid leukemia (AML). Significant changes in cell type proportions and gene expression were observed in AML, indicating disruption of the entire niche. Predicted interactions between hematopoietic stem and progenitor cells (HSPCs) and other bone marrow cell types were also explored, revealing an expansion of interactions in AML that promote HSPC-cell adhesion, immunosuppression, and cytokine signaling. Transforming growth factor b1 (TGFB1)-related interactions were particularly widespread and were shown to drive AML cell quiescence in vitro. These findings highlight potential mechanisms of enhanced AML-HSPC competitiveness and a skewed microenvironment fostering AML growth.
Article
Medicine, Research & Experimental
Hao Wang, Zhenzhen Lin, Zhe Nian, Wei Zhang, Wenxu Liu, Fei Yan, Zengtuan Xiao, Xia Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu
Summary: The study identifies GFI1 as a critical regulator of anchorage independence in lung cancer cells, revealing a mechanism by which carcinoma cells hijack a hematopoietic factor for gaining anchorage independence. This could lead to ERK signaling dependency in tumor cells, suggesting potential interventions for suppressing metastasis and improving therapeutic outcomes in cancer.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Editorial Material
Cell & Tissue Engineering
Malini Gupta, Britta Will
Summary: Adaptive aberrant gene regulation is a hallmark of malignant growth and therapy resistance in acute myeloid leukemia (AML). In this study, Eagle et al. identified oncogenic enhancer-driven overexpression of selenophosphate synthetase 2 (SEPHS2) as a targeted opportunity for mitigating malignant cell growth in AML.
Article
Medicine, Research & Experimental
Jamie A. Moore, Jayna J. Mistry, Charlotte Hellmich, Rebecca H. Horton, Edyta E. Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth
Summary: The bone marrow microenvironment plays an important role in regulating acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. The researchers found that macrophage LC3-associated phagocytosis (LAP) is the main method of macrophage phagocytosis in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells and bodies, resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived apoptotic bodies by macrophages activated the stimulator of IFN genes (STING) pathway, suppressing the growth of AML.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Review
Oncology
Kristen J. Kurtz, Shannon E. Conneely, Madeleine O'Keefe, Katharina Wohlan, Rachel E. Rau
Summary: Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy. Murine models of AML are indispensable research tools to better understand the mechanisms and test novel therapeutic approaches for this disease.
FRONTIERS IN ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Qianze Dong, Yan Xiu, Yang Wang, Christina Hodgson, Nick Borcherding, Craig Jordan, Jane Buchanan, Eric Taylor, Brett Wagner, Mariah Leidinger, Carol Holman, Dennis J. Thiele, Sean O'Brien, Hai-hui Xue, Jinming Zhao, Qingchang Li, Howard Meyerson, Brendan F. Boyce, Chen Zhao
Summary: The transcription factor HSF1 is specifically required for the maintenance of leukemia stem cells in acute myeloid leukemia (AML), and pharmacologically targeting HSF1 may have broad anti-leukemic effects.
NATURE COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Mary Gudipati, Melody Butler, Rima Koka, Maria R. Baer, Yi Ning
Summary: Heterogeneous subtypes of acute myeloid leukemia (AML) are moving towards a more genetically defined classification. Accurate classification of AML with recurrent chromosomal translocations is important for diagnosis, prognosis, treatment stratification, and residual disease evaluation. This study highlights the identification of variant t(8;V;21) translocations in newly diagnosed AML patients, emphasizing the value of recognizing and detecting cryptic and complex rearrangements involving chromosome band 8q22 using RUNX1::RUNX1T1 FISH.
Article
Oncology
Mukul Mishra, Gatha Thacker, Akshay Sharma, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Shailendra Prasad Verma, Anil Kumar Tripathi, Madan Lal Brahma Bhatt, Arun Kumar Trivedi
Summary: The study finds that GSK3β kinase inhibition can inhibit AML cell growth and promote myeloid differentiation by phosphorylating PU.1 leading to its degradation, thereby inhibiting monocyte-macrophage differentiation.
MOLECULAR CANCER RESEARCH
(2021)
Article
Multidisciplinary Sciences
Thomas R. Jackson, Aini Vuorinen, Laia Josa-Cullere, Katrina S. Madden, Daniel Conole, Thomas J. Cogswell, Isabel V. L. Wilkinson, Laura M. Kettyle, Douzi Zhang, Alison O'Mahony, Deanne Gracias, Lorna McCall, Robert Westwood, Georg C. Terstappen, Stephen G. Davies, Edward W. Tate, Graham M. Wynne, Paresh Vyas, Angela J. Russell, Thomas A. Milne
Summary: This study found that tubulin disruptors can induce differentiation of AML cells, leading to decreased tumor burden and increased survival rates in vivo.
Article
Oncology
Xueyan Chen, Megan Othus, Brent L. Wood, Roland B. Walter, Pamela S. Becker, Mary-Elizabeth Percival, Janis L. Abkowitz, Frederick R. Appelbaum, Elihu H. Estey
Summary: sAML and MDS-EB share many similarities, including similar mutation distribution and treatment response. This suggests that they may represent different stages or lineages of the same disease.
LEUKEMIA & LYMPHOMA
(2021)
Article
Oncology
Lais Ghiraldeli, Rebecca Anderson, Kristin Pladna, Timothy S. Pardee
Summary: Adenosine monophosphate activated protein kinase (AMPK) plays an important role in chemotherapy response in acute myeloid leukemia (AML). Knocking out AMPK activity in AML cells results in significant resistance to chemotherapy drugs and is associated with shorter survival in patients with low expression of AMPK subunit. Additionally, sensitizing AML cells to chemotherapy can be achieved by activating AMPK.
Article
Biochemistry & Molecular Biology
Xiaoling Xie, Wuju Zhang, Xuan Zhou, Binyan Xu, Hao Wang, Yingqi Qiu, Yuxing Hu, Bin Guo, Zhixin Ye, Le Hu, Honghao Zhang, Yuhua Li, Xiaochun Bai
Summary: Low serum IFN-gamma levels are associated with a higher percentage of LSCs and greater relapse incidence in AML patients. High doses of IFN-gamma have an anti-AML effect, while low doses accelerate AML development and support LSC self-renewal. Targeting IFNGR1 in AML cells induces differentiation and delays leukemogenesis.
Article
Hematology
Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steve Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro M. Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Mueller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H. Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Sator Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G. Kulasekararaj, Lucy A. Godley, Jaroslaw P. Maclejewski, Seishi Ogawa
Summary: DDX41 gene mutations play an important role in late-onset myeloid neoplasms, but many crucial features of DDX41-mutated neoplasms still need to be elucidated. This study comprehensively characterized DDX41-mutated neoplasms and found that DDX41 risk variants accounted for 80% of known genetic predispositions to myeloid neoplasms in adults. Additionally, DDX41 risk alleles were significantly enriched in Japanese cases and more prominent in males compared to females.
Article
Cardiac & Cardiovascular Systems
Canxia Shi, Joseph Pierre Aboumsallem, Navin Suthahar, Aniek O. de Graaf, Joop H. Jansen, Isabelle A. van Zeventer, Valentina Bracun, Sanne de Wit, Elles M. Screever, Pieter F. van den Berg, Wouter C. Meijers, Ron T. Gansevoort, Stephan J. L. Bakker, Pim van der Harst, Herman H. W. Sillje, Gerwin Huls, Rudolf A. de Boer
Summary: This study aimed to analyze the association between clonal hematopoiesis of indeterminate potential (CHIP) and incident heart failure (HF) in a European population cohort. Results showed that CHIP mutations were correlated with age, smoking, hypertension, and cardiovascular biomarkers, but the frequency of CHIP was similar between individuals with incident HF and control participants. However, among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort and significantly associated with new-onset HF.
EUROPEAN JOURNAL OF HEART FAILURE
(2023)
Article
Hematology
Carin L. E. Hazenberg, Aniek O. de Graaf, Rene Mulder, Laura B. Bungener, Andre B. Mulder, Goda Choi, Jan Jacob Schuringa, Marco R. de Groot, Edo Vellenga, Joop H. Jansen, Gerwin Huls, Isabelle A. van Zeventer
Summary: Inadequate mobilization of peripheral blood progenitor cells (PBPCs) is a limiting factor in autologous hematopoietic cell transplantation (auto-HCT). A study investigated the characteristics of poor mobilizers and the impact of clonal hematopoiesis (CH) on mobilization failure. The presence of CH did not associate with poor mobilization potential, but TP53 mutations and PPM1D mutations were associated with poor mobilization potential.
Article
Hematology
Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Recher, Christoph Roellig, Martin Bornhaeuser, Hubert Serve, Carsten Mueller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, Brunangelo Falini
Summary: The characteristics of therapy-related NPM1-mutated AML (t-NPM1 AML) were found to be similar to de novo NPM1-mutated AML (dn-NPM1 AML) in terms of genetics, transcriptional profile, and clinical outcomes. However, t-NPM1 AML showed better overall survival and relapse-free survival compared to t-AML.
Letter
Hematology
Priscilla Kamphuis, Isabelle A. A. van Zeventer, Aniek O. O. de Graaf, Jonas B. B. Salzbrunn, Maaike G. J. M. van Bergen, Avinash G. G. Dinmohamed, Bert A. A. van der Reijden, Jan Jacob Schuringa, Joop H. H. Jansen, Gerwin Huls
Article
Hematology
Priscilla Kamphuis, Maaike G. J. M. van Bergen, Isabelle A. van Zeventer, Aniek O. de Graaf, Avinash G. Dinmohamed, Jonas B. Salzbrunn, Jan Jacob Schuringa, Bert A. van der Reijden, Gerwin Huls, Joop H. Jansen
Summary: Clonal hematopoiesis (CH) may increase the risk of hematological malignancies and overall survival in individuals with platelet count abnormalities. Thrombocytopenia cases showed enrichment of mutations in spliceosome genes, while thrombocytopenia with multiple mutated genes (TP53 or spliceosome genes) increased the risk of death. Thrombocytosis cases had a higher prevalence of CH, with mutations in JAK2 and CALR associated with thrombocytosis.
Article
Hematology
Marieke J. A. Verhagen, Waander L. van Heerde, Johanna G. van der Bom, Erik A. M. Beckers, Nicole M. A. Blijlevens, Michiel Coppens, Samantha C. Gouw, Joop H. Jansen, Frank W. G. Leebeek, Lize F. D. van Vulpen, Danielle Meijer, Saskia E. M. Schols
Summary: The association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia was investigated. The study found that thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals, and a decreased thrombin generation profile was associated with a severe clinical bleeding phenotype.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Oncology
Isabelle A. van Zeventer, Aniek O. de Graaf, Jonas B. Salzbrunn, Ilja M. Nolte, Priscilla Kamphuis, Avinash Dinmohamed, Bert A. van der Reijden, Jan Jacob Schuringa, Joop H. Jansen, Gerwin Huls
Summary: Knowledge about the evolution of clonal hematopoiesis is crucial for clinical decision-making. This study investigated clonal evolution in a large cohort and found that spliceosome and JAK2 mutations have the highest growth rates, while DNMT3A and TP53 mutations show minimal growth, regardless of cytosis or cytopenia. Individual variability suggests modulation by non-mutation-related factors. The risk for myeloid malignancy is highest for JAK2, spliceosome, or TP53 mutations and is preceded by cytosis or cytopenia. These findings provide important insights for monitoring and managing clonal hematopoiesis and related disorders.
Article
Oncology
Margot F. van Spronsen, Diana Hanekamp, Theresia M. Westers, Noortje van Gils, Eline Vermue, Arjo Rutten, Joop H. Jansen, Birgit I. Lissenberg-Witte, Linda Smit, Gerrit J. Schuurhuis, Arjan A. van de Loosdrecht
Summary: Myelodysplastic syndromes (MDS) are hematological disorders originating from neoplastic transformation of hematopoietic stem cells (HSCs). This study highlights the presence of immunophenotypic aberrant HSCs (IA-HSCs) in MDS-derived bone marrows (MDS-BMs), which predict leukemic progression and show potential as a prognostic biomarker. IA-HSCs are associated with perturbed hematopoiesis and independent of conventional risk factors. The sensitivity and specificity of IA-HSCs for predicting leukemic progression at 2 years follow-up were 83% and 71%, respectively.
Letter
Oncology
Saioa Arza-Apalategi, Branco M. H. Heuts, Meike T. M. Dooijes, Daan Gilissen, Adrian J. P. van der Heijden, Joop H. Jansen, Joost H. A. Martens, Bert A. van der Reijden
Article
Oncology
Michael Oertel, Tom Schlusemann, Evgenii Shumilov, Gabriele Reinartz, Anne Bremer, Stephan Rehn, Georg Lenz, Cyrus Khandanpour, Hans Theodor Eich
Summary: This study evaluated the tolerability of concurrent radiotherapy and targeted therapy. The results showed that radiotherapy is safe and feasible in the treatment of multiple myeloma, but careful monitoring of potential toxicities is necessary.
Article
Hematology
Stuart Scott, Richard Dillon, Christian Thiede, Sadia Sadiq, Ashley Cartwright, Hazel J. Clouston, Debbie Travis, Katya Mokretar, Nicola Potter, Andrew Chantry, Liam Whitby
Summary: The European LeukaemiaNet (ELN) MRD working group has published guidelines for standardizing molecular genetic MRD testing of certain markers. A study involving 29 international laboratories showed that most participants were able to accurately detect and interpret MRD testing results, although some errors were identified. False-positive results were reported in the NPM1 marker-negative samples, emphasizing the need for ongoing quality assessment and proficiency testing. The study also highlighted the need for revising the guidelines to address interpretive issues and improve dissemination.
Article
Oncology
P. K. J. D. de Jonge, P. M. M. van Hauten, L. D. Janssen, A. L. de Goede, M. M. Berrien-Elliott, J. M. R. van der Meer, C. M. Mousset, M. W. H. Roeven, M. Foster, N. Blijlevens, W. Hobo, T. A. Fehniger, J. H. Jansen, N. P. M. Schaap, H. Dolstra
Summary: Allogeneic natural killer (NK) cell-based immunotherapy is a promising approach for acute myeloid leukemia (AML). A good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34(+) hematopoietic stem and progenitor cells (HSPC) has been developed. This process generates a consistent and active NK cell product that meets the requirements for NK cell immunotherapy. The manufactured NK cell batches are used in a clinical trial approved by the Dutch Ethics Committee.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Jesper van Eck van der Sluijs, Diede van Ens, Jolanda Brummelman, Daan Heister, Aastha Sareen, Lisa Truijen, Dorette S. van Ingen Schenau, Mirjam H. M. Heemskerk, Marieke Griffioen, Michel G. D. Kester, Nicolaas P. M. Schaap, Joop H. Jansen, Anniek B. van der Waart, Harry Dolstra, Willemijn Hobo
Summary: Non-DCs have been found to enhance the activation and expansion of antigen-specific CD8+ T cells mediated by DCs, without impairing the NK cell responses in vitro and in vivo. This provides a rationale for further clinical translation of the CD34+-derived DC-complete vaccine in hemato-oncology patients post alloSCT.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Oncology
Lisa B. Leypoldt, Maria Gavriatopoulou, Britta Besemer, Hans Salwender, Marc S. Raab, Axel Nogai, Cyrus Khandanpour, Volker Runde, Anna Jauch, Manola Zago, Peter Martus, Hartmut Goldschmidt, Carsten Bokemeyer, Meletios A. Dimopoulos, Katja C. Weisel
Summary: This study evaluated the safety and efficacy of daratumumab, bortezomib, and dexamethasone in multiple myeloma patients with severe renal function impairment. The treatment showed an overall response rate of 67% and improved renal function in patients. This study suggests that this treatment regimen could be considered in the clinical practice for multiple myeloma patients with severe renal function impairment.