bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–11–07
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia.
  2. A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation.
  3. Acute Myeloid Leukemia Epigenetic Immune Escape From Nature Killer Cells by ICAM-1.
  4. 2021 Update Measurable Residual Disease in Acute Myeloid Leukemia: European LeukemiaNet Working Party Consensus Document.
  5. Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia.
  6. Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
  7. The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis.
  8. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities.
  9. TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
  10. Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation.
  11. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models.
  12. A prospective biomarker analysis of alvocidib followed by cytarabine and mitoxantrone in MCL-1-dependent relapsed/refractory acute myeloid leukemia.
  13. RUNX1 mutations correlate with response to venetoclax combination therapies in relapsed/refractory acute myeloid leukemia.
  14. Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-ALL.
  15. Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition.
  16. ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol.
  17. Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
  18. Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients.
  19. Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases.
  20. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia.
  21. Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.
  22. Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia in the United States.
  1. Haematologica. 2021 Nov 04.
    AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia.
    Sean M Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J L Aitken, Po Yee Mak, Vivian R Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E Chan, Lauren B Ostermann, Marina Konopleva, Bing Z Carter, Courtney DiNardo, Michael D Andreeff, Joseph D Khoury, Peter P Ruvolo.
      FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in AML. The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor ONO-7475 kills FLT3-mutant acute myeloid leukemia cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single agent in vivo using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO- 7475/ABT-199 was even more potent in reducing leukemic burden and prolonging survival of mice in both model systems. These results suggest the ONO-7475/ABT-199 combination may be effective for acute myeloid leukemia therapy.
    DOI:  https://doi.org/10.3324/haematol.2021.278369
  2. Leukemia. 2021 Nov 03.
    A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation.
    Min Yang, Zengkai Pan, Kezhi Huang, Guntram Büsche, Hongyun Liu, Gudrun Göhring, Regina Rumpel, Oliver Dittrich-Breiholz, Steven Talbot, Michaela Scherr, Anuhar Chaturvedi, Matthias Eder, Julia Skokowa, Jianfeng Zhou, Karl Welte, Nils von Neuhoff, Ligen Liu, Arnold Ganser, Zhixiong Li.
      With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.
    DOI:  https://doi.org/10.1038/s41375-021-01452-6
  3. Front Oncol. 2021 ;11 751834
    Acute Myeloid Leukemia Epigenetic Immune Escape From Nature Killer Cells by ICAM-1.
    Yang Xiao, Jinghong Chen, Jia Wang, Wei Guan, Mengzhen Wang, Linlin Zhang, Zhiding Wang, Lixin Wang, Li Yu.
      Acute myeloid leukemia (AML), a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions, and epigenetic modification, while the mechanism is not clearly understood. Here we show that the expression of Intercellular adhesion molecule-1 (ICAM-1, CD54) is silenced in AML cells. Decitabine could upregulate ICAM-1 expression, which contributes to the NK-AML cell conjugates and helps NK cells kill AML cells. We also show that ICAM-1 high expression can reverse the AML immune evasion and activate NK cells function in vivo. This study suggests that a combination of the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.
    Keywords:  AML; ICAM-1; NK; immune escape; methylation
    DOI:  https://doi.org/10.3389/fonc.2021.751834
  4. Blood. 2021 Nov 01. pii: blood.2021013626. [Epub ahead of print]
    2021 Update Measurable Residual Disease in Acute Myeloid Leukemia: European LeukemiaNet Working Party Consensus Document.
    Michael Heuser, Sylvie D Freeman, Gert J Ossenkoppele, Francesco Buccisano, Christopher S Hourigan, Lok Lam Ngai, Jesse Marc Tettero, Costa Bachas, Constance Baer, Marie C Béné, Veit Buecklein, Anna Czyz, Barbara Denys, Richard Dillon, Michaela Feuring-Buske, Monica L Guzman, Torsten Haferlach, Lina Han, Julia K Herzig, Jeffrey L Jorgensen, Wolfgang Kern, Marina Y Konopleva, Francis Lacombe, Marta Libura, Agata Majchrzak, Luca Maurillo, Yishai Ofran, Jan Philippé, Adriana Plesa, Claude Preudhomme, Farhad Ravandi, Christophe Roumier, Marion Subklewe, Felicitas Thol, Arjan A van de Loosdrecht, Bert A van der Reijden, Adriano Venditti, Agnieszka Wierzbowska, Peter J M Valk, Brent L Wood, Roland B Walter, Christian Thiede, Konstanze Döhner, Gail J Roboz, Jacqueline Cloos.
      Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a two-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next generation sequencing (NGS)-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate endpoint for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular- MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.
    DOI:  https://doi.org/10.1182/blood.2021013626
  5. Blood Adv. 2021 Nov 03. pii: bloodadvances.2021006047. [Epub ahead of print]
    Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia.
    Jana Krosl, Marie-Eve Bordeleau, Céline Moison, Tara MacRae, Isabel Boivin, Nadine Mayotte, Deanne Gracias, Irène Baccelli, Vincent-Philippe Lavallée, Richard Bisaillon, Bernhard Lehnertz, Rodrigo Mendoza-Sanchez, Réjean Ruel, Thierry Bertomeu, Jasmin Coulombe-Huntington, Geneviève Boucher, Nandita Noronha, Caroline Pabst, Mike Tyers, Patrick Gendron, Sébastien Lemieux, Frédéric Barabé, Anne Marinier, Josée Hébert, Guy Sauvageau.
      Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006047
  6. Bio Protoc. 2021 Oct 05. 11(19): e4171
    Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
    Nick van Gastel, Jessica B Spinelli, Marcia C Haigis, David T Scadden.
      Once thought to be a mere consequence of the state of a cell, intermediary metabolism is now recognized as a key regulator of mammalian cell fate and function. In addition, cell metabolism is often disturbed in malignancies such as cancer, and targeting metabolic pathways can provide new therapeutic options. Cell metabolism is mostly studied in cell cultures in vitro, using techniques such as metabolomics, stable isotope tracing, and biochemical assays. Increasing evidence however shows that the metabolic profile of cells is highly dependent on the microenvironment, and metabolic vulnerabilities identified in vitro do not always translate to in vivo settings. Here, we provide a detailed protocol on how to perform in vivo stable isotope tracing in leukemia cells in mice, focusing on glutamine metabolism in acute myeloid leukemia (AML) cells. This method allows studying the metabolic profile of leukemia cells in their native bone marrow niche.
    Keywords:  Cancer biology; Cell metabolism; Glutamine; Leukemia; Metabolic tracing; Mouse models
    DOI:  https://doi.org/10.21769/BioProtoc.4171
  7. Leukemia. 2021 Nov 05.
    The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis.
    Christiaan J Stavast, Iris van Zuijen, Elena Karkoulia, Arman Özçelik, Antoinette van Hoven-Beijen, Leticia G Leon, Jane S A Voerman, George M C Janssen, Peter A van Veelen, Monika Burocziova, Rutger W W Brouwer, Wilfred F J van IJcken, Alex Maas, Eric M Bindels, Vincent H J van der Velden, Christopher Schliehe, Peter D Katsikis, Meritxell Alberich-Jorda, Stefan J Erkeland.
      MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.
    DOI:  https://doi.org/10.1038/s41375-021-01461-5
  8. Front Immunol. 2021 ;12 775128
    Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities.
    Tony Marchand, Sandra Pinho.
      Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. While complete remission can be obtained with intensive chemotherapy in young and fit patients, relapse is frequent and prognosis remains poor. Leukemic cells are thought to arise from a pool of leukemic stem cells (LSCs) which sit at the top of the hierarchy. Since their discovery, more than 30 years ago, LSCs have been a topic of intense research and their identification paved the way for cancer stem cell research. LSCs are defined by their ability to self-renew, to engraft into recipient mice and to give rise to leukemia. Compared to healthy hematopoietic stem cells (HSCs), LSCs display specific mutations, epigenetic modifications, and a specific metabolic profile. LSCs are usually considered resistant to chemotherapy and are therefore the drivers of relapse. Similar to their HSC counterpart, LSCs reside in a highly specialized microenvironment referred to as the "niche". Bidirectional interactions between leukemic cells and the microenvironment favor leukemic progression at the expense of healthy hematopoiesis. Within the niche, LSCs are thought to be protected from genotoxic insults. Improvement in our understanding of LSC gene expression profile and phenotype has led to the development of prognosis signatures and the identification of potential therapeutic targets. In this review, we will discuss LSC biology in the context of their specific microenvironment and how a better understanding of LSC niche biology could pave the way for new therapies that target AML.
    Keywords:  acute myeloid leukemia; genetic heterogeneity; leukemic stem cell (LSC); stem cell niche; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2021.775128
  9. Diagn Pathol. 2021 Oct 31. 16(1): 100
    TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
    Pimjai Niparuck, Pornnapa Police, Phichchapha Noikongdee, Kanchana Siriputtanapong, Nittaya Limsuwanachot, Budsaba Rerkamnuaychoke, Suporn Chuncharunee, Teerapong Siriboonpiputtana.
       OBJECTIVES: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients.
    METHODS: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA).
    RESULTS: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20-7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32-4.16) and complex karyotype (P = 0.038, HR = 1.07-9.78) were associated with shorter OS in AML patients.
    DISCUSSION: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.
    Keywords:  Acute myeloid leukemia; Myelodysplastic syndrome; T-AML/MDS, complex karyotype, monosomy; TP53 mutation
    DOI:  https://doi.org/10.1186/s13000-021-01162-8
  10. Nat Commun. 2021 Nov 03. 12(1): 6323
    Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation.
    Yuxuan Liu, Zhimin Gu, Hui Cao, Pranita Kaphle, Junhua Lyu, Yuannyu Zhang, Wenhuo Hu, Stephen S Chung, Kathryn E Dickerson, Jian Xu.
      Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid lineage-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid neoplasms with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically deregulate gene expression. We integrate results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooperation at single-cell and single-gene levels, and identify GEM as a regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution at single-cell resolution in vivo.
    DOI:  https://doi.org/10.1038/s41467-021-26582-4
  11. Leukemia. 2021 Nov 05.
    Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models.
    Avik Dutta, Dipmoy Nath, Yue Yang, Bao T Le, Mohammad Ferdous-Ur Rahman, Patrick Faughnan, Zhenjia Wang, Matthew Stuver, Rongquan He, Wuwei Tan, Robert E Hutchison, Jason M Foulks, Steven L Warner, Chongzhi Zang, Golam Mohi.
      Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, we show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis and splenomegaly, and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-β signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.
    DOI:  https://doi.org/10.1038/s41375-021-01464-2
  12. Blood Cancer J. 2021 Oct 30. 11(10): 175
    A prospective biomarker analysis of alvocidib followed by cytarabine and mitoxantrone in MCL-1-dependent relapsed/refractory acute myeloid leukemia.
    Joshua F Zeidner, Tara L Lin, Carlos E Vigil, Gil Fine, M Yair Levy, Aziz Nazha, Jordi Esteve, Daniel J Lee, Karen Yee, Andrew Dalovisio, Eunice S Wang, Juan M Bergua Burgues, Jeffrey Schriber, Mark R Litzow, Olga Frankfurt, Teresa Bernal Del Castillo, Vijaya Raj Bhatt, Bhavana Bhatnagar, Priyanka Mehta, Richard Dillon, Maria Vidriales Vicente, Stephen Anthony, David Bearss, Pau Montesinos, B Douglas Smith.
      
    DOI:  https://doi.org/10.1038/s41408-021-00568-3
  13. Leuk Res. 2021 Oct 23. pii: S0145-2126(21)01736-7. [Epub ahead of print]111 106735
    RUNX1 mutations correlate with response to venetoclax combination therapies in relapsed/refractory acute myeloid leukemia.
    Signy Chow, Kenny Tang, Mahmood Al-Abri, Victoria Hall, Rosemarie Tremblay-Lemay, Iran Rashedi, Hubert Tsui, Steven M Chan.
      
    DOI:  https://doi.org/10.1016/j.leukres.2021.106735
  14. Front Immunol. 2021 ;12 746492
    Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-ALL.
    Juan Carlos Balandrán, José Dávila-Velderrain, Antonio Sandoval-Cabrera, Gabriela Zamora-Herrera, Vanessa Terán-Cerqueda, Lilia Adela García-Stivalet, José Alejandro Limón-Flores, Erick Armenta-Castro, Aurora Rodríguez-Martínez, Bertha Alicia Leon-Chavez, Verónica Vallejo-Ruiz, Duane C Hassane, Sonia Mayra Pérez-Tapia, Vianney Ortiz-Navarrete, Monica L Guzman, Rosana Pelayo.
      B-cell acute lymphoblastic leukemia (B-ALL) results from the expansion of malignant lymphoid precursors within the bone marrow (BM), where hematopoietic niches and microenvironmental signals provide leukemia-initiating cells (LICs) the conditions to survive, proliferate, initiate disease, and relapse. Normal and malignant lymphopoiesis are highly dependent on the BM microenvironment, particularly on CXCL12-abundant Reticular (CAR) cells, which provide a niche for maintenance of primitive cells. During B-ALL, leukemic cells hijack BM niches, creating a proinflammatory milieu incompetent to support normal hematopoiesis but favoring leukemic proliferation. Although the lack of a phenotypic stem cell hierarchy is apparent in B-ALL, LICs are a rare and quiescent population potentially responsible for chemoresistance and relapse. Here, we developed novel patient-derived leukemia spheroids (PDLS), an ex vivo avatar model, from mesenchymal stromal cells (MSCs) and primary B-ALL cells, to mimic specialized niche structures and cell-to-cell intercommunication promoting normal and malignant hematopoiesis in pediatric B-ALL. 3D MSC spheroids can recapitulate CAR niche-like hypoxic structures that produce high levels of CXCL10 and CXCL11. We found that PDLS were preferentially enriched with leukemia cells displaying functional properties of LICs, such as quiescence, low reactive oxygen species, drug resistance, high engraftment in immunodeficient mice, and long-term leukemogenesis. Moreover, the combination of PDLS and patient-derived xenografts confirmed a microenvironment-driven hierarchy in their leukemic potential. Importantly, transcriptional profiles of MSC derived from primary patient samples revealed two unique signatures (1), a CXCL12low inflammatory and leukemia expansion (ILE)-like niche, that likely supports leukemic burden, and (2) a CXCL11hi immune-suppressive and leukemia-initiating cell (SLIC)-like niche, where LICs are likely sustained. Interestingly, the CXCL11+ hypoxic zones were recapitulated within the PDLS that are capable of supporting LIC functions. Taken together, we have implemented a novel PDLS system that enriches and supports leukemia cells with stem cell features driven by CXCL11+ MSCs within hypoxic microenvironments capable of recapitulating key features, such as tumor reemergence after exposure to chemotherapy and tumor initiation. This system represents a unique opportunity for designing ex vivo personalized avatars for B-ALL patients to evaluate their own LIC pathobiology and drug sensitivity in the context of the tumor microenvironment.
    Keywords:  B-cell development; acute lymphoblastic leukemia; bone marrow niche; leukemia-initiating cell; mesenchymal stromal cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.746492
  15. Sci Rep. 2021 Nov 04. 11(1): 21689
    Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition.
    Thanh-Trang Vo, Lee-Or Herzog, Roberta Buono, Jong-Hoon Scott Lee, Sharmila Mallya, Madeleine R Duong, Joshua Thao, Moran Gotesman, David A Fruman.
      The mechanistic target of rapamycin (mTOR) is a kinase whose activation is associated with poor prognosis in pre-B cell acute lymphoblastic leukemia (B-ALL). These and other findings have prompted diverse strategies for targeting mTOR signaling in B-ALL and other B-cell malignancies. In cellular models of Philadelphia Chromosome-positive (Ph+) B-ALL, mTOR kinase inhibitors (TOR-KIs) that inhibit both mTOR-complex-1 (mTORC1) and mTOR-complex-2 (mTORC2) enhance the cytotoxicity of tyrosine kinase inhibitors (TKIs) such as dasatinib. However, TOR-KIs have not shown substantial efficacy at tolerated doses in blood cancer clinical trials. Selective inhibition of mTORC1 or downstream effectors provides alternative strategies that may improve selectivity towards leukemia cells. Of particular interest is the eukaryotic initiation factor 4F (eIF4F) complex that mediates cap-dependent translation. Here we use novel chemical and genetic approaches to show that selective targeting of either mTORC1 kinase activity or components of the eIF4F complex sensitizes murine BCR-ABL-dependent pre-B leukemia cells to dasatinib. SBI-756, a small molecule inhibitor of eIF4F assembly, sensitizes human Ph+ and Ph-like B-ALL cells to dasatinib cytotoxicity without affecting survival of T lymphocytes or natural killer cells. These findings support the further evaluation of eIF4F-targeted molecules in combination therapies with TKIs in B-ALL and other blood cancers.
    DOI:  https://doi.org/10.1038/s41598-021-00950-y
  16. Blood Adv. 2021 Nov 03. pii: bloodadvances.2021005717. [Epub ahead of print]
    ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol.
    Francesco Buccisano, Raffaele Palmieri, Alfonso Piciocchi, Valentina Arena, Anna Candoni, Lorella Melillo, Valeria Calafiore, Roberto Cairoli, Paolo De Fabritiis, Gabriella Storti, Prassede Salutari, Francesco Lanza, Giovanni Martinelli, Mario Luppi, Saveria Capria, Luca Maurillo, Maria Ilaria Del Principe, Giovangiacinto Paterno, Maria Antonietta Irno Consalvo, Tiziana Ottone, Serena Lavorgna, Maria Teresa Voso, Paola Fazi, Marco Vignetti, William Arcese, Adriano Venditti.
      The 2017 version of the ELN recommendations, by integrating cytogenetics and mutational status of specific genes, sort out patients with Acute Myeloid Leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR) and adverse (ELN2017-AR). We performed a post-hoc analysis of the GIMEMA AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive autologous stem cell transplant (AuSCT) if categorized as favorable-risk or allogeneic stem cell transplant (ASCT) if adverse-risk. Intermediate-risk pts were to receive AuSCT or ASCT based on the post-consolidation levels of Measurable Residual Disease as measured by flow-cytometry. Risk categorization was originally conducted according to NCCN2009 recommendations. Among 500 patients, 445 (89%) were re-classified according to the ELN2017 criteria: ELN2017-FR (186/455; 41.8%), ELN2017-IR (179/445 40.2%) and ELN2017-AR (80/455; 18%); in 55 patients (11%) ELN2017 was not applicable (ELN2017-NC). Two-year overall survival (OS) was 68.8%, 51.3%, 45.8% and 42.8% for ELN2017-FR, ELN2017-IR, ELN2017-NC, and ELN2017-AR group, respectively (p<0.001). When comparing the two different transplant strategies in each ELN2017 risk category, a significant benefit of AuSCT over ASCT was observed among ELN2017-FR patients (2-years OS of 83.3% vs. 66.7%; p=0.0421). The two transplant procedures performed almost equally in the ELN2017-IR group (2-years OS of 73.9% vs. 70.8%; p=0.5552). This post-hoc analysis of the GIMEMA AML1310 trial, confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005717
  17. Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01384-X. [Epub ahead of print]37(5): 109911
    Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
    Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon.
      Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
    Keywords:  CAR T cells; DNA methylation; T cell differentiation; TCA cycle; Th1; Treg; lipidome; mitochondrial metabolism; triacylglyceride synthesis; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2021.109911
  18. Blood Cancer J. 2021 Nov 05. 11(11): 176
    Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients.
    Joan How, Charlotte Story, Siyang Ren, Donna Neuberg, Rachel P Rosovsky, Gabriela S Hobbs, Jean M Connors.
      Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5-9.5%) and 12.3% (6.4-18.2%) respectively. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1-3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.
    DOI:  https://doi.org/10.1038/s41408-021-00566-5
  19. Br J Haematol. 2021 Nov 03.
    Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases.
    Ayalew Tefferi, Jaya Kittur, Faiqa Farrukh, Kebede H Begna, Mrinal M Patnaik, Aref Al-Kali, Michelle A Elliott, Kaaren K Reichard, Naseema Gangat, Animesh Pardanani.
      We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment-emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.
    Keywords:  2-chlorodeoxyadenosine; KIT; avapritinib; midostaurin; mutation
    DOI:  https://doi.org/10.1111/bjh.17932
  20. Blood. 2021 Nov 01. pii: blood.2021012895. [Epub ahead of print]
    HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia.
    Yoshitaka Zaimoku, Bhavisha A Patel, Sharon D Adams, Ruba N Shalhoub, Emma M Groarke, Audrey Ai Chin Lee, Sachiko Kajigaya, Xingmin Feng, Olga Julia Rios, Holly Eager, Lemlem Alemu, Diego Quinones Raffo, Colin O Wu, Willy A Flegel, Neal S Young.
      Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined somatic loss of HLA class I alleles, and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In two patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.
    DOI:  https://doi.org/10.1182/blood.2021012895
  21. Nat Commun. 2021 Nov 03. 12(1): 6340
    Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.
    Manish Kumar, David Molkentine, Jessica Molkentine, Kathleen Bridges, Tongxin Xie, Liangpeng Yang, Andrew Hefner, Meng Gao, Reshub Bahri, Annika Dhawan, Mitchell J Frederick, Sahil Seth, Mohamed Abdelhakiem, Beth M Beadle, Faye Johnson, Jing Wang, Li Shen, Timothy Heffernan, Aakash Sheth, Robert L Ferris, Jeffrey N Myers, Curtis R Pickering, Heath D Skinner.
      Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.
    DOI:  https://doi.org/10.1038/s41467-021-26570-8
  22. Blood Adv. 2021 Nov 01. pii: bloodadvances.2021005642. [Epub ahead of print]
    Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia in the United States.
    Jan Philipp Bewersdorf, Stephanie Prozora, Nikolai A Podoltsev, Rory Michael Shallis, Scott F Huntington, Natalia Neparidze, Rong Wang, Amer M Zeidan, Amy J Davidoff.
      Acute promyelocytic leukemia (APL) is associated with a favorable long-term prognosis if appropriate treatment is initiated promptly. Outcomes in clinical trials and population-based registries vary; potential explanations include a delay in treatment and lower adherence to guideline-recommended therapy in real-world practice. We used the Vizient Clinical Data Base (CDB) to describe demographics, baseline clinical characteristics, and treatment patterns in newly diagnosed APL patients during the study period of April 2017 - March 2020. Baseline white blood cell count (WBC) was used to assign risk status and assess treatment concordance with National Comprehensive Cancer Network guidelines. Logistic regression models examined adjusted associations between patient, hospital, disease characteristics, and adverse outcomes (in-hospital death or discharge to hospice). Among 1,464 APL patients, 205 (14.0%) experienced an adverse outcome. A substantial subset (20.6%) of patients did not receive guideline-concordant regimens. Odds of adverse outcomes increased with failure to receive guideline-concordant treatment (OR: 2.31 [95% CI: 1.43 - 3.75]; p=0.001), high-risk disease (OR: 2.48 [1.53 - 4.00]; p<0.001) and increasing age (≥60 years: OR: 11.13 [95% CI: 4.55 - 27.22]; p<0.001). Higher hospital AML patient volume was associated with lower odds of adverse outcome (OR: 0.44 [0.20 - 0.99] for ≤ 50 vs. >200 AML patients/year; p=0.046). In conclusion, in this large database analysis, 14.0% of newly diagnosed APL patients died or were discharged to hospice. A substantial proportion of patients did not receive guideline-concordant therapy, potentially contributing to adverse outcomes.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005642
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