bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–01–01
twenty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia.
  2. High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.
  3. DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.
  4. HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.
  5. Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.
  6. Relative Mitochondrial Priming Predicts Survival in Older AML Patients Treated Intensively.
  7. Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
  8. An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia.
  9. DNA polymerase theta protects leukemia cells from metabolic-induced DNA damage.
  10. Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.
  11. Comparison of reduced intensity and nonmyeloablative conditioning for adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation in first or second remission.
  12. ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.
  13. Impact of Center-related Characteristics and Macroeconomic Factors on the Outcome of Adult Patients With Acute Lymphoblastic Leukemia Treated With Pediatric-inspired Protocols.
  14. Clinical and molecular characteristics associated with Vitamin C deficiency in myeloid malignancies; real world data from a prospective cohort.
  15. Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance.
  16. Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
  17. Impact of the International Consensus Classification of myelodysplastic syndromes.
  18. Erythropoiesis in lower-risk myelodysplastic syndromes and beta-thalassemia.
  19. Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of GvHD.
  20. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.
  21. Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.
  1. Leukemia. 2022 Dec 26.
    Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia.
    Namrata Rastogi, Juan Bautista Menendez Gonzalez, Vikas Kumar Srivastava, Bader Alanazi, Rehab N Alanazi, Owen M Hughes, Niamh S O'Neill, Amanda F Gilkes, Neil Ashley, Sumukh Deshpande, Robert Andrews, Adam Mead, Neil P Rodrigues, Steve Knapper, Richard L Darley, Alex Tonks.
      Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01801-z
  2. Leukemia. 2022 Dec 30.
    High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.
    Zakia Aid, Elie Robert, Cécile K Lopez, Maxence Bourgoin, Fabien Boudia, Melchior Le Mene, Julie Riviere, Marie Baille, Salima Benbarche, Laurent Renou, Alexandre Fagnan, Cécile Thirant, Laetitia Federici, Laure Touchard, Yann Lecluse, Anton Jetten, Birgit Geoerger, Hélène Lapillonne, Eric Solary, Muriel Gaudry, Soheil Meshinchi, Françoise Pflumio, Patrick Auberger, Camille Lobry, Arnaud Petit, Arnaud Jacquel, Thomas Mercher.
      Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2+ leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2+ leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup.
    DOI:  https://doi.org/10.1038/s41375-022-01800-0
  3. Nat Cancer. 2022 Dec 29.
    DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.
    Tim Kong, Angelo B A Laranjeira, Kangning Yang, Daniel A C Fisher, LaYow Yu, Laure Poittevin De La Frégonnière, Anthony Z Wang, Marianna B Ruzinova, Jared S Fowles, Mary C Fulbright, Maggie J Cox, Hamza Celik, Grant A Challen, Sidong Huang, Stephen T Oh.
      Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2V617F and MPLW515L MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6-RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies.
    DOI:  https://doi.org/10.1038/s43018-022-00486-8
  4. Blood. 2022 Dec 28. pii: blood.2022016528. [Epub ahead of print]
    HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.
    Shuchi Agrawal-Singh, Jaana Bagri, George Giotopoulos, Dhoyazan Azazi, Sarah J Horton, Cecile K Lopez, Shubha Anand, Anne-Sophie Bach, Frances Stedham, Robin Antrobus, Jack W Houghton, George S Vassiliou, Daniel Sasca, Haiyang Yun, Anthony D Whetton, Brian James Patrick Huntly.
      HOXA9 is commonly upregulated in acute myeloid leukemia (AML), where it confers poor prognosis. Characterising the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein-SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro and prolonged survival in vivo. Integrated genomic, transcriptomic and proteomic analyses further demonstrated that the HOXA9-SAFB-chromatin complex associates with NuRD and HP1g to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPd, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1g -associated catalytic activity also triggered differentiation, apoptosis and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML, that may be amenable to therapeutic intervention via therapies targeting the HOXA9/SAFB interface and/or NuRD and HP1g activity.
    DOI:  https://doi.org/10.1182/blood.2022016528
  5. Ann Hematol. 2022 Dec 28.
    Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.
    Piroska Klement, Walter Fiedler, Razif Gabdoulline, Louisa-Kristin Dallmann, Clara Philine Wienecke, Johannes Schiller, Christian Kandziora, Katrin Teich, Bennett Heida, Konstantin Büttner, Maximilian Brandes, Carolin Funke, Martin Wichmann, Basem Othman, Joerg Chromik, Stefanie Amberg, Maxim Kebenko, Vera Schlipfenbacher, Anne Christine Wilke, Franziska Modemann, Melanie Janning, Hubert Serve, Carsten Bokemeyer, Susann Theile, Ute Deppermann, Anne L Kranich, Arnold Ganser, Felicitas Thol, Michael Heuser.
      Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.
    Keywords:  AML; Molecular patterns; Relapse; Selinexor
    DOI:  https://doi.org/10.1007/s00277-022-05075-4
  6. Hemasphere. 2023 Jan;7(1): e819
    Relative Mitochondrial Priming Predicts Survival in Older AML Patients Treated Intensively.
    Reinaldo Dal Bello, Kim Pacchiardi, Clémentine Chauvel, Lionel Adès, Thorsten Braun, Justine Pasanisi, Elise Fournier, Céline Berthon, Emmanuelle Clappier, Emmanuel Raffoux, Delphine Lebon, Thomas Cluzeau, Christophe Roumier, Adriana Plesa, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Stéphanie Mathis, Alexandre Puissant, Claude Gardin, Raphael Itzykson.
      
    DOI:  https://doi.org/10.1097/HS9.0000000000000819
  7. Leukemia. 2022 Dec 26.
    Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
    Svea Stratmann, Mattias Vesterlund, Husen M Umer, Saeed Eshtad, Aron Skaftason, Morten Krogh Herlin, Christer Sundström, Anna Eriksson, Martin Höglund, Josefine Palle, Jonas Abrahamsson, Kirsi Jahnukainen, Monica Cheng Munthe-Kaas, Bernward Zeller, Katja Pokrovskaja Tamm, Cecilia Lindskog, Lucia Cavelier, Janne Lehtiö, Linda Holmfeldt.
      Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
    DOI:  https://doi.org/10.1038/s41375-022-01796-7
  8. Nat Cancer. 2022 Dec 29.
    An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia.
    Audrey Lasry, Bettina Nadorp, Maarten Fornerod, Deedra Nicolet, Huiyun Wu, Christopher J Walker, Zhengxi Sun, Matthew T Witkowski, Anastasia N Tikhonova, Maria Guillamot-Ruano, Geraldine Cayanan, Anna Yeaton, Gabriel Robbins, Esther A Obeng, Aristotelis Tsirigos, Richard M Stone, John C Byrd, Stanley Pounds, William L Carroll, Tanja A Gruber, Ann-Kathrin Eisfeld, Iannis Aifantis.
      Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric patients with AML. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B-cell subtype enriched in patients with high-inflammation AML, as well as an increase in CD8+GZMK+ and regulatory T cells, accompanied by a reduction in T-cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in patients with AML. Addition of the iScore refines current risk stratifications for patients with AML and may enable identification of patients in need of more aggressive treatment. This work provides a framework for classifying patients with AML based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings.
    DOI:  https://doi.org/10.1038/s43018-022-00480-0
  9. Blood. 2022 Dec 29. pii: blood.2022018428. [Epub ahead of print]
    DNA polymerase theta protects leukemia cells from metabolic-induced DNA damage.
    Umeshkumar Vekariya, Monika Maria Toma, Margaret Nieborowska-Skorska, Bac Viet Le, Marie-Christine Caron, Anna-Mariya Kukuyan, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Kumaraswamy Naidu Chitrala, Jessica Atkins, Malgorzata Drzewiecka, Wanjuan Feng, Joe Chan, Srinivas Chatla, Konstantin Golovine, Jaroslav Jelinek, Tomasz Sliwinski, Jayashri Ghosh, Ksenia Matlawska-Wasowska, Gurushankar Chandramouly, Reza Nejati, Mariusz A Wasik, Stephen Sykes, Katarzyna Piwocka, Emir Hadzijusufovic, Peter Valent, Richard T Pomerantz, George Morton, Wayne Childers, Huaqing Zhao, Elisabeth Paietta, Ross L Levine, Martin S Tallman, Hugo Fernandez, Mark R Litzow, Gaorav Gupta, Jean-Yves Masson, Tomasz Skorski.
      Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.
    DOI:  https://doi.org/10.1182/blood.2022018428
  10. Hemasphere. 2023 Jan;7(1): e818
    Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.
    Adrián Mosquera-Orgueira, Manuel Pérez-Encinas, Alberto Hernández-Sánchez, Teresa González-Martínez, Eduardo Arellano-Rodrigo, Javier Martínez-Elicegui, Ángela Villaverde-Ramiro, José-María Raya, Rosa Ayala, Francisca Ferrer-Marín, María-Laura Fox, Patricia Velez, Elvira Mora, Blanca Xicoy, María-Isabel Mata-Vázquez, María García-Fortes, Anna Angona, Beatriz Cuevas, María-Alicia Senín, Angel Ramírez-Payer, María-José Ramírez, Raúl Pérez-López, Sonia González de Villambrosía, Clara Martínez-Valverde, María-Teresa Gómez-Casares, Carmen García-Hernández, Mercedes Gasior, Beatriz Bellosillo, Juan-Luis Steegmann, Alberto Álvarez-Larrán, Jesús María Hernández-Rivas, Juan Carlos Hernández-Boluda.
      Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.
    DOI:  https://doi.org/10.1097/HS9.0000000000000818
  11. Bone Marrow Transplant. 2022 Dec 28.
    Comparison of reduced intensity and nonmyeloablative conditioning for adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation in first or second remission.
    Roland B Walter, Brenda M Sandmaier, Megan Othus, Corentin Orvain, Eduardo Rodríguez-Arbolí, Masumi U Oshima, Gary Schoch, Chris Davis, H Joachim Deeg, Rainer Storb.
      Reduced intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning regimens have expanded use of allogeneic hematopoietic cell transplantation (HCT) in AML to include older and medically less-fit patients, but relative efficacies and toxicities remain poorly defined. Here, we analyzed outcomes from 343 adults transplanted in remission after RIC (n = 137) or NMA (n = 206) conditioning between 2006 and 2021. The characteristics of RIC and NMA HCT patients were similar except that RIC patients were younger and their time between most recent remission achievement and allografting was shorter. There were no significant differences in relapse risk, relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM) between RIC and NMA HCT patients, both overall (relapse: hazard ratio [HR] = 0.80, P = 0.27; RFS: HR = 0.93, P = 0.61; OS: HR = 0.93, P = 0.66; NRM: HR = 1.13, P = 0.59) and when patients were stratified by pre-HCT measurable residual disease (MRD) status. After multivariable adjustment, there was no statistically significant association between conditioning intensity and relapse (HR = 0.69, P = 0.088), RFS (HR = 0.86, P = 0.37), OS (HR = 0.89, P = 0.49), or NRM (HR = 1.37, P = 0.19). In this non-randomized cohort of adults undergoing allografting for AML in first or second remission at our center, we could not detect statistically significant differences in outcomes between those assigned to RIC and those assigned to NMA conditioning.
    DOI:  https://doi.org/10.1038/s41409-022-01909-x
  12. Cancer. 2022 Dec 29.
    ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.
    Wen Shuai, Zhuang Zuo, Nianyi Li, Sofia Garces, Fatima Zahra Jelloul, Chi Young Ok, Shaoying Li, Jie Xu, M James You, Wei Wang, Catherine Rehder, Elias J Jabbour, Keyur P Patel, L Jeffrey Medeiros, C Cameron Yin.
       BACKGROUND: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms.
    METHODS: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms.
    RESULTS: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow-up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation.
    CONCLUSIONS: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease-specific and should be interpreted with caution to classify myeloid neoplasms.
    Keywords:  acute myeloid leukemia (AML), ethanolamine kinase 1 (ETNK1), myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasm (MDS/MPN), myeloproliferative neoplasm (MPN)
    DOI:  https://doi.org/10.1002/cncr.34616
  13. Hemasphere. 2023 Jan;7(1): e810
    Impact of Center-related Characteristics and Macroeconomic Factors on the Outcome of Adult Patients With Acute Lymphoblastic Leukemia Treated With Pediatric-inspired Protocols.
    Pere Barba, Mireia Morgades, Pau Montesinos, Jose Gonzalez-Campos, Anna Torrent, Cristina Gil, Teresa Bernal, Mar Tormo, Santiago Mercadal, Sandra Novoa, Irene García-Cadenas, M Paz Queipo de Llano, Marta Cervera, Rosa Coll, Arancha Bermudez, M Luz Amigo, Silvia Monsalvo, Jordi Esteve, Raimundo Garcia-Boyero, Andres Novo, Jesús Maria Hernandez Rivas, Antonia Cladera, Pilar Martinez-Sanchez, Josefina Serrano, Maria Teresa Artola, Beatriz Soria, Eugenia Abella, Ferran Vall-Llovera, Juan Bergua, Pilar Herrera, Daniel Barrios, Josep Maria Ribera.
      
    DOI:  https://doi.org/10.1097/HS9.0000000000000810
  14. Leuk Res. 2022 Dec 21. pii: S0145-2126(22)00377-0. [Epub ahead of print]125 107001
    Clinical and molecular characteristics associated with Vitamin C deficiency in myeloid malignancies; real world data from a prospective cohort.
    Naveen Premnath, Stephen S Chung, Olga K Weinberg, Ruth Ikpefan, Mohak Pandey, Gurbakhash Kaur, Praveen Ramakrishnan Geethakumari, Aimaz Afrough, Farrukh T Awan, Larry D Anderson, Madhuri Vusirikala, Robert H Collins, Weina Chen, Michalis Agathocleous, Yazan F Madanat.
      Vitamin C is an essential vitamin that acts as a co-factor for many enzymes involved in epigenetic regulation in humans. Low vitamin C levels in hematopoietic stem cells (HSC) promote self-renewal and vitamin C supplementation retards leukaemogenesis in vitamin C-deficient mouse models. Studies on vitamin C levels in patients with myeloid malignancies are limited. We thus conducted a retrospective analysis on a prospective cohort of patients with myeloid malignancies on whom plasma vitamin C levels were measured serially at diagnosis and during treatment. Baseline characteristics including hematological indices, cytogenetics, and molecular mutations are described in this cohort. Among 64 patients included in our study, 11 patients (17%) had low vitamin C levels. We noted a younger age at diagnosis for patients with myeloid malignancies who had low plasma vitamin C levels. Patients with low plasma vitamin C levels were more likely to have acute myeloid leukemia compared to other myeloid malignancies. Low vitamin C levels were associated with ASXL1 mutations. Our study calls for further multi-institutional studies to understand the relevance of low plasma vitamin C level in myeloid neoplasms, the role of vitamin C deficiency in leukemogenesis, and the potential benefit of vitamin C supplementation.
    Keywords:  AML; ASXL1; Clonal hematopoiesis of indeterminate potential; Myeloid neoplasm; TET2; Vitamin C deficiency
    DOI:  https://doi.org/10.1016/j.leukres.2022.107001
  15. Cell Stem Cell. 2022 Dec 17. pii: S1934-5909(22)00487-8. [Epub ahead of print]
    Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance.
    Ying Cheng, Zhuying Gao, Tiantian Zhang, Yuhua Wang, Xueqin Xie, Guoqiang Han, Yashu Li, Rong Yin, Yilin Chen, Peipei Wang, Jin Hu, Tong Zhang, Chengli Guo, Jihua Chai, Jing Wang, Manman Cui, Kexin Gao, Weidong Liu, Shuxin Yao, Pengbo Lu, Ziyan Cao, Yanbing Zheng, Jiwei Chang, Zheming Liu, Qibin Song, Weiming Li, Fuling Zhou, Haojian Zhang.
      N6-methyladenosine (m6A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m6A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m6A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m6A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 and m6A reader IGF2BP2 maintain the function of human and murine leukemia stem cells (LSCs). Genetic deletion or pharmacological inhibition of PRMT6 damages AML development and LSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m6A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoic acid levels and impairs LSC maintenance. Collectively, our findings reveal a critical role of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategy for targeting LSCs.
    Keywords:  IGF2BP2; PRMT6; RNA m(6)A; acute myeloid leukemia; leukemia stem cells
    DOI:  https://doi.org/10.1016/j.stem.2022.12.003
  16. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209062120
    Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
    Jiaxin Wu, Juan Li, Kang Chen, Guolong Liu, Yating Zhou, Wenqi Chen, Xiangzhan Zhu, Terri T Ni, Bianhong Zhang, Daqing Jin, Dali Li, Lan Kang, Yuxuan Wu, Ping Zhu, Peng Xie, Tao P Zhong.
      Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage. We find that Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling. During hematopoiesis, the interaction of Atf7ip and Setdb1 triggers H3K9me3 depositions in hematopoietic regulatory genes including cebpβ and cdkn1a, preventing HSPCs from loss of expansion and premature differentiation into myeloid lineage. Concomitantly, loss of Atf7ip or Setdb1 derepresses retrotransposons that instigate the viral sensor Mda5/Rig-I like receptor (RLR) signaling, leading to stress-driven myelopoiesis and inflammation. We find that ATF7IP or SETDB1 depletion represses human leukemic cell growth and induces myeloid differentiation with retrotransposon-triggered inflammation. These findings establish that Atf7ip/Setdb1-mediated H3K9me3 deposition constitutes a genome-wide checkpoint that impedes the myeloid potential and maintains HSPC stemness for diverse blood cell production, providing unique insights into potential intervention in hematological malignancy.
    Keywords:  HSPC; epigenetics; leukemia; myeloid differentiation; retrotransposon
    DOI:  https://doi.org/10.1073/pnas.2209062120
  17. Br J Haematol. 2022 Dec 28.
    Impact of the International Consensus Classification of myelodysplastic syndromes.
    Yudi Zhang, Junying Wu, Zefeng Xu, Tiejun Qin, Shiqiang Qu, Lijuan Pan, Huijun Wang, Qi Sun, Chengwen Li, Yujiao Jia, Wenyu Cai, Xin Yan, Jingye Gong, Qingyan Gao, Bing Li, Robert Peter Gale, Zhijian Xiao.
      The impact of the 2022 International Consensus Classification (ICC) of myelodysplastic syndromes (MDS) needs study. We analysed data from 989 MDS subjects classified using the 2016 World Health Organization (WHO) criteria to determine the impact of the new proposal. Our analyses suggested the ICC criteria of MDS-SF3B1 identifies a more homogenous disease entity than the WHO 2016 criteria of myelodysplastic syndromes with ring sideroblasts (MDS-RS). MDS, not otherwise specified with single lineage dysplasia (MDS, NOS-SLD) patients had a better prognosis than MDS, NOS with multilineage dysplasia (MDS, NOS-MLD) patients. MDS with mutated TP53 and MDS/acute myeloid leukaemia with mutated TP53 patients had the briefest survivals. These data support the ICC of MDS, which allows more accurate diagnoses and risk stratification.
    Keywords:  International Consensus Classification; World Health Organization classification; myelodysplastic syndromes; prognostic
    DOI:  https://doi.org/10.1111/bjh.18628
  18. Blood Rev. 2022 Dec 22. pii: S0268-960X(22)00113-8. [Epub ahead of print] 101039
    Erythropoiesis in lower-risk myelodysplastic syndromes and beta-thalassemia.
    Maria Domenica Cappellini, Ali T Taher, Amit Verma, Farrukh Shah, Olivier Hermine.
      The hematologic disorders myelodysplastic syndromes and beta-thalassemia are characterized by ineffective erythropoiesis and anemia, often managed with regular blood transfusions. Erythropoiesis, the process by which sufficient numbers of functional erythrocytes are produced from hematopoietic stem cells, is highly regulated, and defects can negatively affect the proliferation, differentiation, and survival of erythroid precursors. Treatments that directly target the underlying mechanisms of ineffective erythropoiesis are limited, and management of anemia with regular blood transfusions imposes a significant burden on patients, caregivers, and health care systems. There is therefore a strong unmet need for treatments that can restore effective erythropoiesis. Novel therapies are beginning to address this need by targeting a variety of mechanisms underlying erythropoiesis. Herein, we provide an overview of the role of ineffective erythropoiesis in myelodysplastic syndromes and beta-thalassemia, discuss unmet needs in targeting ineffective erythropoiesis, and describe current management strategies and emerging treatments for these disorders.
    Keywords:  Anemia; Erythropoiesis; Iron overload; Myelodysplastic syndromes; Novel therapies; β-Thalassemia
    DOI:  https://doi.org/10.1016/j.blre.2022.101039
  19. Blood. 2022 Dec 27. pii: blood.2022017982. [Epub ahead of print]
    Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of GvHD.
    Juliane K Lohmeyer, Toshihito Hirai, Mustafa Turkoz, Stephane Buhler, Teresa Lopes Ramos, Natalie Köhler, Jeanette Baker, Astrid Melotti, Ingrid Wagner, Amandine Pradier, Sisi Wang, Xuhuai Ji, Simone Becattini, Jean Villard, Doron Merkler, Yves Chalandon, Robert S Negrin, Federico Simonetta.
      CD4+FOXP3+ regulatory T cells have demonstrated efficacy in graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCRa, TCRb genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal restriction and that Treg did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire, however, markedly suppressed their expansion. Transcriptomic analysis revealed that Treg predominantly affected the transcriptome of CD4 Tcon and to a lesser extent of CD8 Tcon, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.
    DOI:  https://doi.org/10.1182/blood.2022017982
  20. Nat Cancer. 2022 Dec 30.
    The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.
    Anita Villani, Scott Davidson, Nisha Kanwar, Winnie W Lo, Yisu Li, Sarah Cohen-Gogo, Fabio Fuligni, Lisa-Monique Edward, Nicholas Light, Mehdi Layeghifard, Ricardo Harripaul, Larissa Waldman, Bailey Gallinger, Federico Comitani, Ledia Brunga, Reid Hayes, Nathaniel D Anderson, Arun K Ramani, Kyoko E Yuki, Sasha Blay, Brittney Johnstone, Cara Inglese, Rawan Hammad, Catherine Goudie, Andrew Shuen, Jonathan D Wasserman, Rosemarie E Venier, Marianne Eliou, Miranda Lorenti, Carol Ann Ryan, Michael Braga, Meagan Gloven-Brown, Jianan Han, Maria Montero, Famida Spatare, James A Whitlock, Stephen W Scherer, Kathy Chun, Martin J Somerville, Cynthia Hawkins, Mohamed Abdelhaleem, Vijay Ramaswamy, Gino R Somers, Lianna Kyriakopoulou, Johann Hitzler, Mary Shago, Daniel A Morgenstern, Uri Tabori, Stephen Meyn, Meredith S Irwin, David Malkin, Adam Shlien.
      We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.
    DOI:  https://doi.org/10.1038/s43018-022-00474-y
  21. Nat Cancer. 2022 Dec 29.
    Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.
    Claudia M Denkinger, Maike Janssen, Ulrike Schäkel, Julia Gall, Albrecht Leo, Patrick Stelmach, Stefan F Weber, Johannes Krisam, Lukas Baumann, Jacek Stermann, Uta Merle, Markus A Weigand, Christian Nusshag, Lars Bullinger, Jens-Florian Schrezenmeier, Martin Bornhäuser, Nael Alakel, Oliver Witzke, Timo Wolf, Maria J G T Vehreschild, Stefan Schmiedel, Marylyn M Addo, Felix Herth, Michael Kreuter, Phil-Robin Tepasse, Bernd Hertenstein, Mathias Hänel, Anke Morgner, Michael Kiehl, Olaf Hopfer, Mohammad-Amen Wattad, Carl C Schimanski, Cihan Celik, Thorsten Pohle, Matthias Ruhe, Winfried V Kern, Anita Schmitt, Hanns-Martin Lorenz, Margarida Souto-Carneiro, Mary Gaeddert, Niels Halama, Stefan Meuer, Hans-Georg Kräusslich, Barbara Müller, Paul Schnitzler, Sylvia Parthé, Ralf Bartenschlager, Martina Gronkowski, Jennifer Klemmer, Michael Schmitt, Peter Dreger, Katharina Kriegsmann, Richard F Schlenk, Carsten Müller-Tidow.
      Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 (n = 134) within four risk groups ((1) cancer (n = 56); (2) immunosuppression (n = 16); (3) laboratory-based risk factors (n = 36); and (4) advanced age (n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer (P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.
    DOI:  https://doi.org/10.1038/s43018-022-00503-w
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