Editorial Material
Hematology
Sara E. Meyer
Summary: In this issue of Blood, Li et al.1 explore the role of FLT3 internal tandem duplication (ITD) in orchestrating transcriptional and epigenetic programs in myeloid progenitor cells, resulting in distinct functional outputs.
Article
Biochemistry & Molecular Biology
Shun-Suke Sakai, Atsushi Hasegawa, Ryosuke Ishimura, Naoki Tamura, Shun Kageyama, Satoko Komatsu-Hirota, Manabu Abe, Yiwei Ling, Shujiro Okuda, Manabu Funayama, Mika Kikkawa, Yoshiki Miura, Kenji Sakimura, Ichiei Narita, Satoshi Waguri, Ritsuko Shimizu, Masaaki Komatsu
Summary: A study found that the copy number duplication of ATG2B and GSKIP genes is associated with myeloproliferative neoplasm (MPN). Mice lacking both Atg2b and Gskip genes showed decreased hematopoiesis, leading to fetal death and anemia. The number of hematopoietic stem cells (HSCs), especially long-term HSCs, was significantly decreased due to increased cell death. The results demonstrate the synergistic effect of Atg2b and Gskip in maintaining the pool size of HSCs.
MOLECULAR AND CELLULAR BIOLOGY
(2022)
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Oncology
Jasmin Straube, Theresa Eifert, Therese Vu, Yashaswini Janardhanan, Rohit Haldar, Bjoern von Eyss, Leanne Cooper, Claudia Bruedigam, Victoria Y. Ling, Emily Cooper, Ann-Marie Patch, Lars Bullinger, Tina M. Schnoeder, Megan Bywater, Florian H. Heidel, Steven W. Lane
Summary: Murine models are useful for studying AML subtypes and compound mutations. The Cre recombinase expression in a transgenic murine model can lead to aggressive leukemia phenotype, polyclonal expansion of FLT3(ITD/ITD) progenitor cells, differentiation block and activation of Myc-dependent gene expression programs. Our report highlights the potential risks and unexpected effects of Cre expression in investigating oncogenic mutations in murine cancer models.
Article
Oncology
Pierre-Yves Dumas, Arnaud Villacreces, Amelie V. Guitart, Ali El-habhab, Layal Massara, Olivier Mansier, Audrey Bidet, Delphine Martineau, Solene Fernandez, Thibaut Leguay, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, Vanessa Desplat
Summary: The study revealed that gilteritinib exhibited a stronger proapoptotic effect on FLT3-ITD AML cells in a simulated bone marrow microenvironment compared to quizartinib, and was more effective at targeting leukemia cells. Additionally, gilteritinib showed a toxicity profile on normal murine hematopoiesis similar to quizartinib.
CLINICAL CANCER RESEARCH
(2021)
Article
Multidisciplinary Sciences
Lu Cui, Ignacio Moraga, Tristan Lerbs, Camille Van Neste, Stephan Wilmes, Naotaka Tsutsumi, Aaron Claudius Trotman-Grant, Milica Gakovic, Sarah Andrews, Jason Gotlib, Spyros Darmanis, Martin Enge, Stephen Quake, Ian S. Hitchcock, Jacob Piehler, K. Christopher Garcia, Gerlinde Wernig
Summary: The study developed a series of surrogate protein ligands that can modulate TPO-R signaling, preserving HSC properties and inhibiting oncogenic signaling through TPO-R by tuning downstream responses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Hematology
Barbara Spitzer, Filemon S. Dela Cruz, Glorymar D. Ibanez Sanchez, Yanming Zhang, Wenbin Xiao, Ryma Benayed, Alina Markova, M. Irene Rodriguez-Sanchez, Nancy Bouvier, Mikhail Roshal, Andrew L. Kung, Neerav Shukla
Summary: MLN-Eo is a WHO-established category of hematologic malignancies, and we report a case of an 8-month-old infant diagnosed with ETV6-FLT3 driven MLN-Eo who achieved complete remission after treatment. This case highlights the clinical utility of ex vivo drug testing in targeted therapies.
Article
Oncology
Shaowei Qiu, Harish Kumar, Chengcheng Yan, Hui Li, Andrew J. Paterson, Nicholas R. Anderson, Jianbo He, Jing Yang, Min Xie, David K. Crossman, Rui Lu, Robert S. Welner, Ravi Bhatia
Summary: The FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML). FLT3 tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy but fail to target leukemia stem cells (LSC) and do not generate sustained responses. Autophagy plays an important role in regulating FLT3-ITD AML stem cell function and response to TKI treatment. Autophagy inhibition reduces the quiescence and repopulating potential of FLT3-ITD AML LSC, while TKI treatment reduces mitochondrial respiration and counteracts the effects of autophagy inhibition on LSC. The targeting of AML LSC and progenitor cells by TKIs is p53-dependent, enhanced by autophagy inhibition in progenitors but reduced in LSC, suggesting a potential alternative approach to target AML LSC quiescence and regenerative potential.
Review
Biochemistry & Molecular Biology
Yammy Yung, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip, Harinder Gill
Summary: Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders characterized by clonal myeloproliferation. Despite effective treatment, complete eradication of CML/MPN stem cells is rare. Novel agents and combination therapy have potential to target abnormal hematopoietic stem cells and the sustaining bone marrow microenvironment in CML and MPNs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Letter
Biophysics
Emily C. Liang, Connie Chen, Rong Lu, Gabriel N. Mannis, Lori Muffly
Summary: Measurable residual disease is associated with poor prognosis in AML, and new NGS methods are highly sensitive in detecting MRD. The use of FLT3 inhibitors post-HCT is crucial for maintaining remission. Early post-HCT MRD negatively impacts PFS, while maintenance FLT3 inhibitors lead to superior PFS and OS for both MRD-negative and MRD-positive patients.
BONE MARROW TRANSPLANTATION
(2021)
Article
Hematology
Nan Wang, Jing Yin, Na You, Shangda Yang, Dan Guo, Yangyang Zhao, Yongxin Ru, Xiaoyan Liu, Hui Cheng, Qian Ren, Tao Cheng, Xiaotong Ma
Summary: The transcription factor TWIST1 is identified as a critical regulator of HSC maintenance by modulating mitochondrial function. Deletion of Twist1 leads to decreased HSC frequency, impaired self-renewal capacity, skewed myeloid differentiation, and compromised stress tolerance. The mechanism involves activation of voltage-gated calcium channel Cacna1b, resulting in increased mitochondrial calcium levels, metabolic activity, and reactive oxygen species production, which can be rescued by calcium channel blocker under stress conditions.
Article
Oncology
Haotian Zhang, Amar Yeware, Sandy Lee, Huichun Zhan
Summary: This study demonstrates that a murine model with both JAK2V617F-bearing hematopoietic cells and JAK2V617F-bearing vascular ECs can recapitulate key features of human MPN disease. The findings suggest that the spleen plays a crucial role in JAK2V617F mutant neoplastic hematopoiesis during aging and MPN disease progression. Additionally, the presence of JAK2V617F-bearing vascular ECs may contribute to both hematologic and cardiovascular abnormalities in MPN.
FRONTIERS IN ONCOLOGY
(2021)
Article
Cell & Tissue Engineering
Yukai Lu, Zihao Zhang, Song Wang, Yan Qi, Fang Chen, Yang Xu, Mingqiang Shen, Mo Chen, Naicheng Chen, Lijing Yang, Shilei Chen, Fengchao Wang, Yongping Su, Mengjia Hu, Junping Wang
Summary: Srebf1c gene plays a crucial role in regulating the fate of hematopoietic stem cells by modulating the activity of the TSC1-mTOR-mitochondria axis to restrain excessive activation of mitochondrial metabolism.
Article
Oncology
Zihao Zhang, Yukai Lu, Yan Qi, Yang Xu, Song Wang, Fang Chen, Mingqiang Shen, Mo Chen, Naicheng Chen, Lijing Yang, Shilei Chen, Fengchao Wang, Yongping Su, Mengjia Hu, Junping Wang
Summary: CDK19 is involved in the regulation of HSC and AML cell proliferation via the p53-p21 pathway.
Article
Biophysics
Zixuan Zhang, Yuta Hasegawa, Daigo Hashimoto, Hajime Senjo, Ryo Kikuchi, Xuanzhong Chen, Kazuki Yoneda, Tomoko Sekiguchi, Tatsuya Kawase, Hirofumi Tsuzuki, Takashi Ishio, Takahide Ara, Hiroyuki Ohigashi, Masao Nakagawa, Takanori Teshima
Summary: This study found that short-term administration of the selective FLT3 inhibitor, gilteritinib, after allo-SCT can enhance the immune response against FLT3-ITD+ leukemia and significantly improve survival rate.
BONE MARROW TRANSPLANTATION
(2022)
Article
Biochemistry & Molecular Biology
Chun-Wei Chen, Richard P. Koche, Amit U. Sinha, Aniruddha J. Deshpande, Nan Zhu, Rowena Eng, John G. Doench, Haiming Xu, Scott H. Chu, Jun Qi, Xi Wang, Christopher Delaney, Kathrin M. Bernt, David E. Root, William C. Hahn, James E. Bradner, Scott A. Armstrong
Article
Medicine, Research & Experimental
Nan Zhu, Mo Chen, Rowena Eng, Joshua DeJong, Amit U. Sinha, Noushin F. Rahnamay, Richard Roche, Fatima Al-Shahrour, Janna C. Minehart, Chun-Wei Chen, Aniruddha J. Deshpande, Haiming Xu, S. Haihua Chu, Benjamin L. Ebert, Robert G. Roeder, Scott A. Armstrong
JOURNAL OF CLINICAL INVESTIGATION
(2016)
Review
Pharmacology & Pharmacy
S. Haihua Chu, Donald Small
DRUG RESISTANCE UPDATES
(2009)
Editorial Material
Multidisciplinary Sciences
S. Haihua Chu, Scott A. Armstrong