bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–03–07
39 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
  2. The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia.
  3. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.
  4. Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics.
  5. OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.
  6. Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients.
  7. Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.
  8. UPDATE ON DRUG TRANSPORTER PROTEINS IN ACUTE MYELOID LEUKEMIA: PATHOLOGICAL IMPLICATION AND CLINICAL SETTING.
  9. JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.
  10. Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.
  11. Mayo Clinic experience with 1123 adults with acute myeloid leukemia.
  12. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment.
  13. Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia.
  14. 1-C Metabolism-Serine, Glycine, Folates-In Acute Myeloid Leukemia.
  15. Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.
  16. Expression levels of HLA-DR in acute myeloid leukemia: implications for antigenicity and clinical outcome.
  17. Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy.
  18. Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments.
  19. Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine.
  20. Genetics of Myeloproliferative Neoplasms.
  21. Single-cell DNA sequencing reveals complex mechanisms of resistance to quizartinib.
  22. The prognosis and durable clearance of RAS mutations in patients with acute myeloid leukemia receiving induction chemotherapy.
  23. Epigenetic Dysregulation of Myeloproliferative Neoplasms.
  24. Accelerated and Blast Phase Myeloproliferative Neoplasms.
  25. Overview of Myeloproliferative Neoplasms: History, Pathogenesis, Diagnostic Criteria, and Complications.
  26. GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia.
  27. Discovery of a Novel CIP2A Variant (NOCIVA) with clinical relevance in predicting TKI resistance in myeloid leukemias.
  28. Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors.
  29. CRISPR screens in physiologic medium reveal conditionally essential genes in human cells.
  30. Efficacy of 10-day decitabine in acute myeloid leukemia.
  31. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia.
  32. The pathobiology of thrombosis, microvascular disease, and hemorrhage in the myeloproliferative neoplasms.
  33. Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival.
  34. Should I rock the boat? When to stop TKIs in CML.
  35. Gene expression profile correlates with molecular and clinical features in patients with myelofibrosis.
  36. Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms.
  37. Disruption of CSF-1R signaling inhibits growth of AML with inv(16).
  38. Glasdegib in combination with low-dose Cytarabine for the outpatient treatment of relapsed or refractory acute myeloid leukemia in unfit patients.
  39. Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate.
  1. Cancer Cell. 2021 Mar 03. pii: S1535-6108(21)00108-2. [Epub ahead of print]
    MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
    Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C Wheat, Oliver Bohorquez, Swathi-Rao Narayanagari, Samuel J Taylor, Luis A Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea Pellagatti, Jacqueline Boultwood, Amit Verma, Ulrich Steidl.
      MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
    Keywords:  CK1α; MDMX; acute myeloid leukemia; cancer interception; myelodysplastic syndromes; precision prevention; preleukemia; preleukemic stem cells; targeted therapy; β-Catenin
    DOI:  https://doi.org/10.1016/j.ccell.2021.02.006
  2. Cancers (Basel). 2021 Feb 28. pii: 1003. [Epub ahead of print]13(5):
    The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia.
    Valentina Gaidano, Mohammad Houshmand, Nicoletta Vitale, Giovanna Carrà, Alessandro Morotti, Valerio Tenace, Stefania Rapelli, Stefano Sainas, Agnese Chiara Pippione, Marta Giorgis, Donatella Boschi, Marco Lucio Lolli, Daniela Cilloni, Alessandro Cignetti, Giuseppe Saglio, Paola Circosta.
      Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity.
    Keywords:  DHODH; acute myeloid leukemia; apoptosis; cancer metabolism; differentiation; dipyridamole; pyrimidine depletion
    DOI:  https://doi.org/10.3390/cancers13051003
  3. Leukemia. 2021 Mar 02.
    Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.
    Richard A Larson, Sumithra J Mandrekar, Lucas J Huebner, Ben L Sanford, Kristina Laumann, Susan Geyer, Clara D Bloomfield, Christian Thiede, Thomas W Prior, Konstanze Döhner, Guido Marcucci, Maria Teresa Voso, Rebecca B Klisovic, Ilene Galinsky, Andrew H Wei, Jorge Sierra, Miguel A Sanz, Joseph M Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R Appelbaum, Bruno C Medeiros, Martin S Tallman, Jürgen Krauter, Richard F Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Insa Gathmann, Hartmut Döhner, Richard M Stone.
      The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
    DOI:  https://doi.org/10.1038/s41375-021-01179-4
  4. Nat Commun. 2021 03 01. 12(1): 1366
    Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics.
    Lars Velten, Benjamin A Story, Pablo Hernández-Malmierca, Simon Raffel, Daniel R Leonce, Jennifer Milbank, Malte Paulsen, Aykut Demir, Chelsea Szu-Tu, Robert Frömel, Christoph Lutz, Daniel Nowak, Johann-Christoph Jann, Caroline Pabst, Tobias Boch, Wolf-Karsten Hofmann, Carsten Müller-Tidow, Andreas Trumpp, Simon Haas, Lars M Steinmetz.
      Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.
    DOI:  https://doi.org/10.1038/s41467-021-21650-1
  5. Blood Cancer J. 2021 Mar 03. 11(3): 48
    OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.
    Bartholomew J Eisfelder, Caner Saygin, Joseph Wynne, Margaret W Colton, Mariafausta Fischietti, Elspeth M Beauchamp, Jason X Cheng, Olatoyosi Odenike, Gail Roboz, Houda Alachkar, Wendy Stock.
      Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.
    DOI:  https://doi.org/10.1038/s41408-021-00433-3
  6. Cell Rep Med. 2021 Feb 16. 2(2): 100202
    Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients.
    Lili Aslostovar, Allison L Boyd, Yannick D Benoit, Justin Di Lu, Juan Luis Garcia Rodriguez, Mio Nakanishi, Deanna P Porras, Jennifer C Reid, Ryan R Mitchell, Brian Leber, Anargyros Xenocostas, Ronan Foley, Mickie Bhatia.
      The aberrant expression of dopamine receptors (DRDs) in acute myeloid leukemia (AML) cells has encouraged the repurposing of DRD antagonists such as thioridazine (TDZ) as anti-leukemic agents. Here, we access patient cells from a Phase I dose escalation trial to resolve the cellular and molecular bases of response to TDZ, and we extend these findings to an additional independent cohort of AML patient samples tested preclinically. We reveal that in DRD2+ AML patients, DRD signaling in leukemic progenitors provides leukemia-exclusive networks of sensitivity that spare healthy hematopoiesis. AML progenitor cell suppression can be increased by the isolation of the positive enantiomer from the racemic TDZ mixture (TDZ+), and this is accompanied by reduced cardiac liability. Our study indicates that the development of DRD-directed therapies provides a targeting strategy for a subset of AML patients and potentially other cancers that acquire DRD expression upon transformation from healthy tissue.
    Keywords:  Phase I trial; QTc interval; acute myeloid leukemia; cyclic AMP; dopamine receptor; leukemic progenitor; targeted therapy; thioridazine; xenograft
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100202
  7. Leukemia. 2021 Mar 02.
    Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.
    Ilaria Gionfriddo, Lorenzo Brunetti, Federica Mezzasoma, Francesca Milano, Valeria Cardinali, Roberta Ranieri, Alessandra Venanzi, Sara Pierangeli, Calogero Vetro, Giulio Spinozzi, Erica Dorillo, Hsin Chieh Wu, Caroline Berthier, Raffaella Ciurnelli, Melanie J Griffin, Claire E Jennings, Enrico Tiacci, Paolo Sportoletti, Franca Falzetti, Hugues de Thé, Gareth J Veal, Maria Paola Martelli, Brunangelo Falini.
      Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.
    DOI:  https://doi.org/10.1038/s41375-021-01192-7
  8. Crit Rev Oncol Hematol. 2021 Mar 02. pii: S1040-8428(21)00069-X. [Epub ahead of print] 103281
    UPDATE ON DRUG TRANSPORTER PROTEINS IN ACUTE MYELOID LEUKEMIA: PATHOLOGICAL IMPLICATION AND CLINICAL SETTING.
    Flavia da Cunha Vasconcelos, Paloma Silva de Souza, Thaís Hancio, Fernanda Costas Casal de Faria, Raquel Ciuvalschi Maia.
      Acute myeloid leukemia (AML) is one of the most common hematological neoplasia causing death worldwide. The long-term overall survival is unsatisfactory due to many factors including older age, genetic heterogeneity and molecular characteristics comprising additional mutations, and resistance to chemotherapeutic drugs. The expression of ABCB1/P-glycoprotein, ABCC1/MRP1, ABCG2/BCRP and LRP transporter proteins is considered the major reason for multidrug resistance (MDR) in AML, however conflicting data have been reported. Here, we review the main issues about drug transporter proteins in AML clinical scenario, and highlight the clinicopathological significance of MDR phenotype associated with ABCB1 polymorphisms and FLT3 mutation.
    Keywords:  ABC transporter protein inhibitors; Acute myeloid leukemia; Drug transporter proteins; Epigenetic; FLT3; Multidrug resistance; Polymorphisms
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103281
  9. Blood. 2021 Feb 24. pii: blood.2020005563. [Epub ahead of print]
    JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.
    Tata Nageswara Rao, Nils Hansen, Jan Stetka, Damien Luque Paz, Milena Kalmer, Julian Hilfiker, Max Endele, Nouraiz Ahmed, Lucia Kubovcakova, Margareta Rybarikova, Hui Hao-Shen, Florian Geier, Christian Beisel, Stefan Dirnhofer, Timm Schroeder, Tim H Brümmendorf, Dominik Wolf, Steffen Koschmieder, Radek C Skoda.
      We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and show bias for differentiation towards megakaryocytes (Mk). Mouse models of myeloproliferative neoplasms (MPN) expressing JAK2-V617F (VF) or a JAK2 exon 12 mutation (E12) displayed increased frequencies and percentages of the CD41hi versusCD41lo HSCs compared to wildtype controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from MPN patients. CD41hi HSCs produced higher numbers of Mk-colonies HSC in single cell cultures in vitro, but showed reduced long-term reconstitution potential compared to CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, while CD41lo HSCs showed higher gene expression of interferon, JAK/STAT and TNFα/NFkB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in MPN patients. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the numbers of JAK2-V617F positive HSCs in mice and patients with MPN. The shift towards the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.
    DOI:  https://doi.org/10.1182/blood.2020005563
  10. Blood Adv. 2021 Mar 09. 5(5): 1442-1451
    Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.
    Damien Luque Paz, Jérémie Riou, Emmanuelle Verger, Bruno Cassinat, Aurélie Chauveau, Jean-Christophe Ianotto, Brigitte Dupriez, Françoise Boyer, Maxime Renard, Olivier Mansier, Anne Murati, Jérôme Rey, Gabriel Etienne, Véronique Mansat-De Mas, Suzanne Tavitian, Olivier Nibourel, Stéphane Girault, Yannick Le Bris, François Girodon, Dana Ranta, Jean-Claude Chomel, Pascale Cony-Makhoul, Pierre Sujobert, Margot Robles, Raouf Ben Abdelali, Olivier Kosmider, Laurane Cottin, Lydia Roy, Ivan Sloma, Fabienne Vacheret, Mathieu Wemeau, Pascal Mossuz, Borhane Slama, Vincent Cussac, Guillaume Denis, Anouk Walter-Petrich, Barbara Burroni, Nathalie Jézéquel, Stéphane Giraudier, Eric Lippert, Gérard Socié, Jean-Jacques Kiladjian, Valérie Ugo.
      We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003444
  11. Blood Cancer J. 2021 Mar 02. 11(3): 46
    Mayo Clinic experience with 1123 adults with acute myeloid leukemia.
    Kebede H Begna, Walid Ali, Naseema Gangat, Michelle A Elliott, Aref Al-Kali, Mark R Litzow, C Christopher Hook, Alexandra P Wolanskyj-Spinner, William J Hogan, Mrinal M Patnaik, Animesh Pardanani, Darci L Zblewski, Dong Chen, Rong He, David Viswanatha, Curtis A Hanson, Rhett P Ketterling, Ayalew Tefferi.
      Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive (n = 766) or lower intensity (n = 144) chemotherapy or supportive care (n = 213), with respective median survivals of 22, 9, and 2 months (p < 0.01). Intensive chemotherapy resulted in complete remission (CR) and CR with incomplete count recovery (CRi) rates of 44 and 33%, respectively, with no difference in survival outcome between the two (p = 0.4). Allogeneic hematopoietic stem cell transplant (AHSCT) was documented in 259 patients and provided the best survival rate (median 55 months; p < 0.01). After a median follow-up of 13 months, 841 (75%) deaths were recorded. Multivariate analysis identified age >60 years (HR 2.2, 1.9-2.6), adverse karyotype (HR 2.9, 1.9-4.9), intermediate-risk karyotype (HR 1.6, 1.02-2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5-2.4), and other secondary AML (HR 1.3 (1.1-1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3+NPM1- (HR 2.8, 1.4-5.6), FLT3+/NPM+ (HR 2.6 (1.3-5.2), and FLT3-NPM1- (HR 1.8, 1.0-3.0).
    DOI:  https://doi.org/10.1038/s41408-021-00435-1
  12. Biomark Res. 2021 Mar 01. 9(1): 15
    Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment.
    Rongqun Guo, Mengdie Lü, Fujiao Cao, Guanghua Wu, Fengcai Gao, Haili Pang, Yadan Li, Yinyin Zhang, Haizhou Xing, Chunyan Liang, Tianxin Lyu, Chunyan Du, Yingmei Li, Rong Guo, Xinsheng Xie, Wei Li, Delong Liu, Yongping Song, Zhongxing Jiang.
       BACKGROUND: Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components.
    METHODS: Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts.
    RESULTS: We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets.
    CONCLUSION: Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.
    Keywords:  Acute myeloid leukemia; Bone marrow; Immune cells; Immune phenotypes; Microenvironment; Myeloid cells; Single-cell RNA sequencing; T lymphocytes
    DOI:  https://doi.org/10.1186/s40364-021-00265-0
  13. Pharmacogenet Genomics. 2021 Mar 05.
    Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia.
    Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, María José Herrero, Rebeca Rodríguez-Veiga, Antonio Solana-Altabella, Blanca Boluda, Octavio Ballesta-López, Isabel Cano, Evelyn Acuña-Cruz, José Cervera, José Luis Poveda, Miguel Ángel Sanz, Salvador F Aliño, Pau Montesinos.
       OBJECTIVES: Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction.
    METHODS: Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients.
    RESULTS: The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013).
    CONCLUSIONS: This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.
    DOI:  https://doi.org/10.1097/FPC.0000000000000431
  14. Pharmaceuticals (Basel). 2021 Feb 26. pii: 190. [Epub ahead of print]14(3):
    1-C Metabolism-Serine, Glycine, Folates-In Acute Myeloid Leukemia.
    Kanwal Mahmood, Ashkan Emadi.
      Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments.
    Keywords:  amino acid metabolism; amino acid restriction in cancer; amino-acid-degrading enzymes; cancer therapy; leukemia
    DOI:  https://doi.org/10.3390/ph14030190
  15. Cancers (Basel). 2021 Feb 11. pii: 748. [Epub ahead of print]13(4):
    Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.
    Hélène Pasquer, Maëlys Tostain, Nina Kaci, Blandine Roux, Lina Benajiba.
      Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients' overall survival. The more recent development of functional genomic studies, pushed by novel molecular biology technologies (short hairpin RNA (shRNA) and CRISPR-Cas9) and bioinformatics tools design on one hand, along with the engineering of humanized physiologically relevant animal models on the other hand, have opened a new genomics era resulting in a greater knowledge of AML physiopathology. Combining descriptive and functional genomics will undoubtedly open the road for an AML cure within the next decades.
    Keywords:  acute myeloid leukemia; genomics; molecular landscape; physio-pathological models; prognosis; targeted therapies
    DOI:  https://doi.org/10.3390/cancers13040748
  16. Leuk Lymphoma. 2021 Mar 02. 1-18
    Expression levels of HLA-DR in acute myeloid leukemia: implications for antigenicity and clinical outcome.
    Malte Roerden, Melanie Märklin, Helmut R Salih, Wolfgang A Bethge, Reinhild Klein, Hans-Georg Rammensee, Annika Nelde, Juliane S Walz.
      Low human leukocyte antigen (HLA)-DR expression might compromise CD4+ T-cell-mediated anti-tumor immunity. Its immunological and clinical significance however remain undefined in non-promyelocytic acute myeloid leukemia (AML). Taking advantage of mass spectrometry-based immunopeptidome analysis of primary AML samples (n = 31), we studied the implications of low HLA-DR expression for antigen presentation and analyzed its association with disease characteristics and survival within a cohort of 399 AML patients. Remarkably, overall HLA-DR/DQ immunopeptidome diversity was preserved in AML with low HLA-DR expression (HLA-DRlow AML) and was associated with a shift in HLA-DR/DQ allotype abundances (HLA-DQ to HLA-DR/DQ ligand ratio 0.36 vs 0.19 in HLA-DRlow and HLA-DRhigh patients, respectively). Consistent with unimpaired antigenicity, survival was similar in HLA-DRlow and HLA-DRhigh patients. Demonstrating for the first time that overall HLA-DR/DQ antigen presentation is preserved in HLA-DRlow AML, our findings provide a rationale for the non-inferior outcome observed in HLA-DRlow AML patients.
    Keywords:  AML; Acute myeloid leukemia; HLA class II; HLA-DR; immunopeptidome; mass spectrometry
    DOI:  https://doi.org/10.1080/10428194.2021.1885659
  17. Nat Chem Biol. 2021 Mar 04.
    Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy.
    Liguo Wang, Xuejing Shao, Tianbai Zhong, Yue Wu, Aixiao Xu, Xiuyun Sun, Hongying Gao, Yongbo Liu, Tianlong Lan, Yan Tong, Xue Tao, Wenxin Du, Wei Wang, Yingqian Chen, Ting Li, Xianbin Meng, Haiteng Deng, Bo Yang, Qiaojun He, Meidan Ying, Yu Rao.
      The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.
    DOI:  https://doi.org/10.1038/s41589-021-00742-5
  18. Cancers (Basel). 2021 Feb 13. pii: 784. [Epub ahead of print]13(4):
    Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments.
    Simona Pagliuca, Carmelo Gurnari, Valeria Visconte.
      Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine.
    Keywords:  HMA failure; MDS; targeted therapies
    DOI:  https://doi.org/10.3390/cancers13040784
  19. Int J Mol Sci. 2021 Feb 26. pii: 2337. [Epub ahead of print]22(5):
    Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine.
    Nienke Visser, Harm Jan Lourens, Gerwin Huls, Edwin Bremer, Valerie R Wiersma.
      Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.
    Keywords:  AML; autophagy; autophagy inhibitors; chloroquine; cytarabine; therapy resistance
    DOI:  https://doi.org/10.3390/ijms22052337
  20. Hematol Oncol Clin North Am. 2021 Apr;pii: S0889-8588(20)30153-2. [Epub ahead of print]35(2): 217-236
    Genetics of Myeloproliferative Neoplasms.
    Jakub Szybinski, Sara C Meyer.
      Myeloproliferative neoplasms are hematopoietic stem cell disorders based on somatic mutations in JAK2, calreticulin, or MPL activating JAK-STAT signaling. Modern sequencing efforts have revealed the genomic landscape of myeloproliferative neoplasms with additional genetic alterations mainly in epigenetic modifiers and splicing factors. High molecular risk mutations with adverse outcomes have been identified and clonal evolution may promote progression to fibrosis and acute myeloid leukemia. JAK2V617F is recurrently detected in clonal hematopoiesis of indeterminate potential with increased risk for vascular events. Insights into the genetics of myeloproliferative neoplasms has facilitated diagnosis and prognostication and poses novel candidates for targeted therapeutic intervention.
    Keywords:  Calreticulin; Genetic alterations; Genetics; Genomics; JAK2; MPL; Myeloproliferative neoplasms
    DOI:  https://doi.org/10.1016/j.hoc.2020.12.002
  21. Blood Adv. 2021 Mar 09. 5(5): 1437-1441
    Single-cell DNA sequencing reveals complex mechanisms of resistance to quizartinib.
    Cheryl A C Peretz, Lisa H F McGary, Tanya Kumar, Hunter Jackson, Jose Jacob, Robert Durruthy-Durruthy, Mark J Levis, Alexander Perl, Benjamin J Huang, Catherine C Smith.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2020003398
  22. Am J Hematol. 2021 Mar 01.
    The prognosis and durable clearance of RAS mutations in patients with acute myeloid leukemia receiving induction chemotherapy.
    Brian J Ball, Meier Hsu, Sean M Devlin, Maria Arcila, Mikhail Roshal, Yanming Zhang, Chris A Famulare, Aaron D Goldberg, Sheng F Cai, Andrew Dunbar, Zachary Epstein-Peterson, Kamal N Menghrajani, Jacob L Glass, Justin Taylor, Aaron D Viny, Sergio S Giralt, Boglarka Gyurkocza, Brian C Shaffer, Roni Tamari, Ross L Levine, Martin S Tallman, Eytan M Stein.
      
    DOI:  https://doi.org/10.1002/ajh.26146
  23. Hematol Oncol Clin North Am. 2021 Apr;pii: S0889-8588(21)00001-0. [Epub ahead of print]35(2): 237-251
    Epigenetic Dysregulation of Myeloproliferative Neoplasms.
    Andrew Dunbar, Young Park, Ross Levine.
      This article reviews the genetic data on epigenetic modifying mutations in myeloproliferative neoplasms and their clinical implications, preclinical studies exploring our current understanding of how mutations in epigenetic modifying proteins cooperate with myeloproliferative neoplasms drivers to promote disease progression, and recent advances in novel therapeutics supporting the role of targeting epigenetic pathways to treat fibrotic progression.
    Keywords:  Epigenetic pathways; Epigenetics of MPN; Fibrotic progression; Myelofibrosis; Myeloproliferative neoplasms; Preclinical studies
    DOI:  https://doi.org/10.1016/j.hoc.2021.01.001
  24. Hematol Oncol Clin North Am. 2021 Apr;pii: S0889-8588(20)30159-3. [Epub ahead of print]35(2): 325-335
    Accelerated and Blast Phase Myeloproliferative Neoplasms.
    Tania Jain, Raajit K Rampal.
      Accelerated and blast phase myeloproliferative neoplasms are advanced stages of the disease with historically a poor prognosis and little improvement in outcomes thus far. The lack of responses to standard treatments likely results from the more aggressive biology reflected by the higher incidence of complex karyotype and high-risk somatic mutations, which are enriched at the time of transformation. Treatment options include induction chemotherapy (7 + 3) as that used on de novo acute myeloid leukemia or hypomethylating agent-based therapy, which has shown similar outcomes. Allogeneic stem cell transplantation remains the only potential for cure.
    Keywords:  Accelerated phase; Acute myeloid leukemia; Blast phase; Myeloproliferative neoplasm
    DOI:  https://doi.org/10.1016/j.hoc.2020.12.008
  25. Hematol Oncol Clin North Am. 2021 Apr;pii: S0889-8588(20)30152-0. [Epub ahead of print]35(2): 159-176
    Overview of Myeloproliferative Neoplasms: History, Pathogenesis, Diagnostic Criteria, and Complications.
    Douglas Tremblay, Abdulraheem Yacoub, Ronald Hoffman.
      Myeloproliferative disorders are a group of diseases morphologically linked by terminal myeloid cell expansion that frequently evolve from one clinical phenotype to another and eventually progress to acute myeloid leukemia. Diagnostic criteria for the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have been established by the World Health Organization and they are recognized as blood cancers. MPNs have a complex and incompletely understood pathogenesis that includes systemic inflammation, clonal hematopoiesis, and constitutive activation of the JAK-STAT pathway. Complications, such as thrombosis and progression to overt forms of myelofibrosis and acute leukemia, contribute significantly to morbidity and mortality of patients with MPN.
    Keywords:  Diagnostic criteria; Essential thrombocythemia; History; Myelofibrosis; Myeloproliferative neoplasms; Polycythemia vera
    DOI:  https://doi.org/10.1016/j.hoc.2020.12.001
  26. Cell Death Dis. 2021 Mar 03. 12(3): 231
    GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia.
    Cheng Zhou, Juan Du, Liang Zhao, Wei Liu, Tianming Zhao, Hui Liang, Peng Fang, Kaixuan Zhang, Hui Zeng.
      Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma-associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.
    DOI:  https://doi.org/10.1038/s41419-021-03504-2
  27. Clin Cancer Res. 2021 Mar 05. pii: clincanres.3679.2020. [Epub ahead of print]
    Discovery of a Novel CIP2A Variant (NOCIVA) with clinical relevance in predicting TKI resistance in myeloid leukemias.
    Eleonora Makela, Karolina Pavic, Taru M Varila, Urpu Salmenniemi, Eliisa Löyttyniemi, Srikar G Nagelli, Tea Ammunét, Veli-Matti Kähäri, Richard E Clark, Laura L Elo, Venkata Kumari Bachanaboyina, Claire M Lucas, Maija Itälä-Remes, Jukka Westermarck.
       PURPOSE: Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56a. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2Asplicing variant, NOCIVA (NOvel CIp2a VAriant).
    EXPERIMENTAL DESIGN: Characterization of CIP2A variants was performed by both 3' and 5' rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.
    RESULTS: NOCIVA contains CIP2A exons 1-13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13 amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56a, but whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVAbut not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.
    CONCLUSIONS: We discovered novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3679
  28. Cell Stem Cell. 2021 Mar 04. pii: S1934-5909(21)00063-1. [Epub ahead of print]28(3): 378-393
    Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors.
    Courtney L Jones, Anagha Inguva, Craig T Jordan.
      Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.
    DOI:  https://doi.org/10.1016/j.stem.2021.02.013
  29. Cell Metab. 2021 Feb 23. pii: S1550-4131(21)00061-9. [Epub ahead of print]
    CRISPR screens in physiologic medium reveal conditionally essential genes in human cells.
    Nicholas J Rossiter, Kimberly S Huggler, Charles H Adelmann, Heather R Keys, Ross W Soens, David M Sabatini, Jason R Cantor.
      Forward genetic screens across hundreds of cancer cell lines have started to define the genetic dependencies of proliferating human cells and how these vary by genotype and lineage. Most screens, however, have been carried out in culture media that poorly reflect metabolite availability in human blood. Here, we performed CRISPR-based screens in traditional versus human plasma-like medium (HPLM). Sets of conditionally essential genes in human cancer cell lines span several cellular processes and vary with both natural cell-intrinsic diversity and the combination of basal and serum components that comprise typical media. Notably, we traced the causes for each of three conditional CRISPR phenotypes to the availability of metabolites uniquely defined in HPLM versus conventional media. Our findings reveal the profound impact of medium composition on gene essentiality in human cells, and also suggest general strategies for using genetic screens in HPLM to uncover new cancer vulnerabilities and gene-nutrient interactions.
    Keywords:  CRISPR; HPLM; conditional gene essentiality; gene-nutrient interaction; genetic screen; physiologic medium
    DOI:  https://doi.org/10.1016/j.cmet.2021.02.005
  30. Leuk Res. 2021 Feb 12. pii: S0145-2126(21)00025-4. [Epub ahead of print]103 106524
    Efficacy of 10-day decitabine in acute myeloid leukemia.
    Ian M Bouligny, Vivek Mehta, Scott Isom, Leslie R Ellis, Rupali R Bhave, Dianna S Howard, Susan Lyerly, Megan Manuel, Sarah Dralle, Bayard L Powell, Timothy S Pardee.
      The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.
    Keywords:  Acute myeloid leukemia; Decitabine; Real world outcomes; Treatment
    DOI:  https://doi.org/10.1016/j.leukres.2021.106524
  31. Blood Adv. 2021 Mar 09. 5(5): 1199-1208
    Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia.
    Antonio Pierini, Loredana Ruggeri, Alessandra Carotti, Franca Falzetti, Simonetta Saldi, Adelmo Terenzi, Claudio Zucchetti, Gianluca Ingrosso, Tiziana Zei, Roberta Iacucci Ostini, Sara Piccinelli, Samanta Bonato, Sara Tricarico, Antonella Mancusi, Sara Ciardelli, Roberto Limongello, Mara Merluzzi, Mauro Di Ianni, Rita Tognellini, Olivia Minelli, Cristina Mecucci, Maria Paola Martelli, Brunangelo Falini, Massimo Fabrizio Martelli, Cynthia Aristei, Andrea Velardi.
      Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day -4 followed by 1 × 106/kg donor conventional T cells on day -1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor-type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #NCT03977103.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003739
  32. Blood. 2021 Mar 01. pii: blood.2020008109. [Epub ahead of print]
    The pathobiology of thrombosis, microvascular disease, and hemorrhage in the myeloproliferative neoplasms.
    Hans C Hasselbalch, Margitta Elvers, Andrew I Schafer.
      Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In these disorders, circulating red cells, leukocytes and platelets, as well as some vascular endothelial cells (ECs), each have abnormalities that are cell-intrinsic to the MPN driver mutations they harbor (e.g. JAK2 V617F). When these cells are activated in the MPNs, their interactions with each other create a highly pro-adhesive and prothrombotic milieu in the circulation that predisposes MPN patients to venous, arterial, and microvascular thrombosis and occlusive disease. Bleeding problems in the MPNs are caused by the MPN blood cell-initiated development of acquired von Willebrand disease. The inflammatory state created by MPN stem cells in their microenvironment extends systemically to amplify the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state in these diseases.
    DOI:  https://doi.org/10.1182/blood.2020008109
  33. Leukemia. 2021 Mar 02.
    Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival.
    Ghaith Abu-Zeinah, Spencer Krichevsky, Tatiana Cruz, Gabriela Hoberman, Diana Jaber, Niamh Savage, Claudia Sosner, Ellen K Ritchie, Joseph M Scandura, Richard T Silver.
      Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single center retrospective study of 470 PV patients compares the myelofibrosis-free survival (MFS) and overall survival (OS) with rIFNα to two other primary treatments, hydroxyurea (HU) and phlebotomy-only (PHL-O). The median age at diagnosis was 54 years (range 20-94) and the median follow-up was 10 years (range 0-45). Two hundred and twenty-nine patients were women (49%) and 208 were high-risk (44%). The primary treatment was rIFNα in 93 (20%), HU in 189 (40%), PHL-O in 133 (28%) and other cytoreductive drugs in 55 (12%). The treatment groups differed by ELN risk score (p < 0.001). In low-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 84%, 65% and 55% respectively (p < 0.001) and 20-year OS was 100%, 85% and 80% respectively (p = 0.44). In high-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 89%, 41% and 36% respectively (p = 0.19) and 20-year OS was 66%, 40%, 14% respectively (p = 0.016). In multivariable analysis, longer time on rIFNα was associated with a lower risk of myelofibrosis (HR: 0.91, p < 0.001) and lower mortality (HR: 0.94, p = 0.012). In conclusion, this study supports treatment of PV with rIFNα to prevent myelofibrosis and potentially prolong survival.
    DOI:  https://doi.org/10.1038/s41375-021-01183-8
  34. Blood. 2021 Mar 04. 137(9): 1136-1137
    Should I rock the boat? When to stop TKIs in CML.
    Aziz Nazha.
      
    DOI:  https://doi.org/10.1182/blood.2020008645
  35. Blood Adv. 2021 Mar 09. 5(5): 1452-1462
    Gene expression profile correlates with molecular and clinical features in patients with myelofibrosis.
    Sebastiano Rontauroli, Sara Castellano, Paola Guglielmelli, Roberta Zini, Elisa Bianchi, Elena Genovese, Chiara Carretta, Sandra Parenti, Sebastian Fantini, Selene Mallia, Lara Tavernari, Stefano Sartini, Margherita Mirabile, Carmela Mannarelli, Francesca Gesullo, Annalisa Pacilli, Daniela Pietra, Elisa Rumi, Silvia Salmoiraghi, Barbara Mora, Laura Villani, Andrea Grilli, Vittorio Rosti, Giovanni Barosi, Francesco Passamonti, Alessandro Rambaldi, Luca Malcovati, Mario Cazzola, Silvio Bicciato, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini.
      Myelofibrosis (MF) belongs to the family of classic Philadelphia-negative myeloproliferative neoplasms (MPNs). It can be primary myelofibrosis (PMF) or secondary myelofibrosis (SMF) evolving from polycythemia vera (PV) or essential thrombocythemia (ET). Despite the differences, PMF and SMF patients are currently managed in the same way, and prediction of survival is based on the same clinical and genetic features. In the last few years, interest has grown concerning the ability of gene expression profiles (GEPs) to provide valuable prognostic information. Here, we studied the GEPs of granulocytes from 114 patients with MF, using a microarray platform to identify correlations with patient characteristics and outcomes. Cox regression analysis led to the identification of 201 survival-related transcripts characterizing patients who are at high risk for death. High-risk patients identified by this gene signature displayed an inferior overall survival and leukemia-free survival, together with clinical and molecular detrimental features included in contemporary prognostic models, such as the presence of high molecular risk mutations. The high-risk group was enriched in post-PV and post-ET MF and JAK2V617F homozygous patients, whereas pre-PMF was more frequent in the low-risk group. These results demonstrate that GEPs in MF patients correlate with their molecular and clinical features, particularly their survival, and represent the proof of concept that GEPs might provide complementary prognostic information to be applied in clinical decision making.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003614
  36. Leukemia. 2021 Mar 03.
    Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms.
    Alexandre Guy, Johanne Poisson, Chloe James.
      Thrombosis, both in arterial and venous territories, is the major complication of myeloproliferative neoplasms and is responsible for a high rate of morbidity and mortality. The currently accepted risk factors are an age over 60 years and a history of thrombosis. However, many complex mechanisms contribute to this increased prothrombotic risk, with involvement of all blood cell types, plasmatic factors, and endothelial cells. Besides, some cardiovascular events may originate from arterial vasospasm that could contribute to thrombotic complications. In this review, we discuss recent results obtained in mouse models in the light of data obtained from clinical studies. We emphasize on actors of thrombosis that are currently not targeted with current therapeutics but could be promising targets, i.e, neutrophil extracellular traps and vascular reactivity.
    DOI:  https://doi.org/10.1038/s41375-021-01170-z
  37. Blood Adv. 2021 Mar 09. 5(5): 1273-1277
    Disruption of CSF-1R signaling inhibits growth of AML with inv(16).
    Alexander Simonis, Norman F Russkamp, Jan Mueller, C Matthias Wilk, Mattheus H E Wildschut, Renier Myburgh, Nicole Wildner-Verhey van Wijk, Rouven Mueller, Stefan Balabanov, Peter J M Valk, Alexandre P A Theocharides, Markus G Manz.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2020003125
  38. Ann Hematol. 2021 Mar 04.
    Glasdegib in combination with low-dose Cytarabine for the outpatient treatment of relapsed or refractory acute myeloid leukemia in unfit patients.
    Andrius Zucenka, Kazimieras Maneikis, Birute Pugaciute, Ugne Ringeleviciute, Austeja Dapkeviciute, Linas Davainis, Guoda Daukelaite, Paulina Burzdikaite, Vytautas Staras, Laimonas Griskevicius.
      We retrospectively collected clinical data on 31 relapsed or refractory acute myeloid leukemia (R/R AML) patients who were treated with outpatient glasdegib and low-dose Cytarabine (LDAraC) at our institution. The median age was 67 years (45-86). The median Eastern Cooperative Oncology Group performance status was 2 (1-3). The patients had previously received a median number of 2 (1-4) treatment lines, 61% (19/31) had been treated with intensive chemotherapy, 29% (9/31) had relapsed after allogeneic stem cell transplantation, and 45% (14/31) had had venetoclax exposure. Adverse cytogenetics were identified in 45% (14/31) of the cases. The CR + CRp rate was 21% (6/29) among evaluable patients. The median overall survival was 3.9 months for all patients. Different median overall survival times were observed in responders, patients achieving stable disease and those diagnosed with progressive disease: not reached vs 3.9 months vs 0.8 months, respectively (p < 0.001). The most common adverse events were pneumonia (29%, 9/31), sepsis (23%, 7/31), and febrile neutropenia (16%, 5/31). Glasdegib + LDAraC is a fairly safe, non-intensive, outpatient regimen inducing complete remission and resulting in prolonged survival in some R/R AML patients.
    Keywords:  AML; Glasdegib; Refractory; Relapsed; Venetoclax
    DOI:  https://doi.org/10.1007/s00277-021-04471-6
  39. Cell Stem Cell. 2021 Mar 04. pii: S1934-5909(21)00061-8. [Epub ahead of print]28(3): 394-408
    Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate.
    Ram Prosad Chakrabarty, Navdeep S Chandel.
      Recent evidence supports the notion that mitochondrial metabolism is necessary for the determination of stem cell fate. Historically, mitochondrial metabolism is linked to the production of ATP and tricarboxylic acid (TCA) cycle metabolites to support stem cell survival and growth, respectively. However, it is now clear that beyond these canonical roles, mitochondria as signaling organelles dictate stem cell fate and function. In this review, we focus on key conceptual ideas on how mitochondria control mammalian stem cell fate and function through reactive oxygen species (ROS) generation, TCA cycle metabolite production, NAD+/NADH ratio regulation, pyruvate metabolism, and mitochondrial dynamics.
    Keywords:  L-2-HG; ROS; TCA cycle; acetyl-CoA; epigenetics; mitochondrial dynamics; pyruvate
    DOI:  https://doi.org/10.1016/j.stem.2021.02.011
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