bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–02–20
twenty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN.
  2. Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.
  3. IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.
  4. High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia.
  5. Gilteritinib in the management of acute myeloid leukemia: Current evidence and future directions.
  6. Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemia.
  7. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody.
  8. Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy.
  9. Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions.
  10. Specific effects of somatic GATA2 zinc finger mutations on erythroid differentiation.
  11. Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML.
  12. ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.
  13. HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.
  14. Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.
  15. Telomerase inhibition on acute myeloid leukemia stem cell induced apoptosis with both intrinsic and extrinsic pathways.
  16. Metabolic determination of cell fate through selective inheritance of mitochondria.
  17. DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding.
  18. The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias.
  19. The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia.
  20. Guiding the Global Evolution of Cytogenetic Testing for Hematologic Malignancies.
  1. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(21)00013-7. [Epub ahead of print]366 83-124
    Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN.
    Sergiu Pasca, Helen T Chifotides, Srdan Verstovsek, Prithviraj Bose.
      Myeloproliferative neoplasms (MPN) have an inherent tendency to evolve to the blast phase (BP), characterized by ≥20% myeloblasts in the blood or bone marrow. MPN-BP portends a dismal prognosis and currently, effective treatment modalities are scarce, except for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in selected patients, particularly those who achieve complete/partial remission. The mutational landscape of MPN-BP differs from de novo acute myeloid leukemia (AML) in several key aspects, such as significantly lower frequencies of FLT3 and DNMT3A mutations, and higher incidence of IDH1/2 and TP53 in MPN-BP. Herein, we comprehensively review the impact of the three signaling driver mutations (JAK2 V617F, CALR exon 9 indels, MPL W515K/L) that constitutively activate the JAK/STAT pathway, and of the other somatic non-driver mutations (epigenetic, mRNA splicing, transcriptional regulators, and mutations in signal transduction genes) that cooperatively or independently promote MPN progression and leukemic transformation. The MPN subtype, harboring two or more high-molecular risk (HMR) mutations (epigenetic regulators and mRNA splicing factors) and "triple-negative" PMF are among the critical factors that increase risk of leukemic transformation and shorten survival. Primary myelofibrosis (PMF) is the most aggressive MPN; and polycythemia vera (PV) and essential thrombocythemia (ET) are relatively indolent subtypes. In PV and ET, mutations in splicing factor genes are associated with progression to myelofibrosis (MF), and in ET, TP53 mutations predict risk for leukemic transformation. The advent of targeted next-generation sequencing and improved prognostic scoring systems for PMF inform decisions regarding allo-HSCT. The emergence of treatments targeting mutant enzymes (e.g., IDH1/2 inhibitors) or epigenetic pathways (BET and LSD1 inhibitors) along with new insights into the mechanisms of leukemogenesis will hopefully lead the way to superior management strategies and outcomes of MPN-BP patients.
    Keywords:  Clonal evolution; Driver mutations; Epigenetic regulators; Essential thrombocythemia (ET); IDH1, IDH2; JAK/STAT pathway; JAK2 V617F; Leukemic transformation; MPN in accelerated phase (MPN-AP); MPN in blast phase (MPN-BP); Myelofibrosis (MF); Non-driver mutations; Polycythemia vera (PV); Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML); RNA splicing factors; TP53; Transcriptional regulators
    DOI:  https://doi.org/10.1016/bs.ircmb.2021.02.008
  2. Blood Adv. 2022 Feb 14. pii: bloodadvances.2021004321. [Epub ahead of print]
    Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.
    Chiara Pirillo, Flora Birch, Floriane Simonne Tissot, Sara Gonzalez Anton, Myriam Haltalli, Valentina Tini, Isabella Y Kong, Cécile Piot, Benjamin Partridge, Costandina Pospori, Karen Keeshan, Salvatore Santamaria, Edwin Hawkins, Brunangelo Falini, Andrea Marra, Delfim Duarte, Chiu Fan Lee, Edward Roberts, Cristina Lo Celso.
      Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix remodeling, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness, therefore we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML infiltration, proliferation and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004321
  3. Leukemia. 2022 Feb 12.
    IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.
    Boaz Nachmias, Dilshad H Khan, Veronique Voisin, Arvind S Mer, Geethu Emily Thomas, Nadav Segev, Jonathan St-Germain, Rose Hurren, Marcela Gronda, Aaron Botham, Xiaoming Wang, Neil Maclean, Ayesh K Seneviratne, Nathan Duong, Changjiang Xu, Andrea Arruda, Elias Orouji, Arash Algouneh, Razqallah Hakem, Liran Shlush, Mark D Minden, Brian Raught, Gary D Bader, Aaron D Schimmer.
      AML cells are arranged in a hierarchy with stem/progenitor cells giving rise to more differentiated bulk cells. Despite the importance of stem/progenitors in the pathogenesis of AML, the determinants of the AML stem/progenitor state are not fully understood. Through a comparison of genes that are significant for growth and viability of AML cells by way of a CRISPR screen, with genes that are differentially expressed in leukemia stem cells (LSC), we identified importin 11 (IPO11) as a novel target in AML. Importin 11 (IPO11) is a member of the importin β family of proteins that mediate transport of proteins across the nuclear membrane. In AML, knockdown of IPO11 decreased growth, reduced engraftment potential of LSC, and induced differentiation. Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.
    DOI:  https://doi.org/10.1038/s41375-022-01513-4
  4. Cancers (Basel). 2022 Jan 19. pii: 486. [Epub ahead of print]14(3):
    High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia.
    Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Annegret Rosemann, Marie Liebmann, Luisa Klotz, Bertram Opalka, Cyrus Khandanpour.
      Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin.
    Keywords:  MLL/AF9; OXPHOS; heterogeneity; metformin
    DOI:  https://doi.org/10.3390/cancers14030486
  5. Leuk Res. 2022 Feb 09. pii: S0145-2126(22)00034-0. [Epub ahead of print]114 106808
    Gilteritinib in the management of acute myeloid leukemia: Current evidence and future directions.
    Eda Nuhoğlu Kantarcı, Ahmet Emre Eşkazan.
      Acute myeloid leukemia (AML) is defined as a highly progressive heterogeneous hematologic malignancy characterized by loss of differentiation with uncontrolled proliferation of progenitor cells. 5-year overall survival rates are as low as 5-10% in adults above 60 years. Until recently, available treatment options for AML had remained mainly unchanged. Along with the development and usage of new generation drugs, novel therapeutic options in various settings began to alter the prognosis of the disease. FMS-like tyrosine kinase 3 (FLT3), a receptor largely expressed in myeloid progenitors, is thought to have a major role in the differentiation and maturation of hematopoietic precursors. Thus, aiming the inhibition of this pathway is gaining profound importance day by day. This review mainly focuses on the FLT3 inhibitor gilteritinib and its utilization in patients with AML. Current data from the most recent trials concerning gilteritinib and new advances are also discussed here.
    Keywords:  AML; Acute myeloid leukemia; FLT3; FMS-like tyrosine kinase 3 inhibitor; Gilteritinib; Relapsed or refractory; Targeted therapies
    DOI:  https://doi.org/10.1016/j.leukres.2022.106808
  6. Blood Cancer Discov. 2022 Feb 16. pii: bloodcandisc.BCD-21-0160-A.2021. [Epub ahead of print]
    Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemia.
    Masayuki Umeda, Jing Ma, Benjamin J Huang, Kohei Hagiwara, Tamara Westover, Sherif Abdelhamed, Juan M Barajas, Melvin E Thomas, Michael P Walsh, Guangchun Song, Liqing Tian, Yanling Liu, Xiaolong Chen, Pandurang Kolekar, Quang Tran, Scott G Foy, Jamie L Maciaszek, Andrew B Kleist, Amanda R Leonti, Bensheng Ju, John Easton, Huiyun Wu, Virginia Valentine, Marcus B Valentine, Yen-Chun Liu, Rhonda E Ries, Jenny L Smith, Evan Parganas, Ilaria Iacobucci, Ryan Hiltenbrand, Jonathan Miller, Jason R Myers, Evadnie Rampersaud, Delaram Rahbarinia, Michael Rusch, Gang Wu, Hiroto Inaba, Yi-Cheng Wang, Todd A Alonzo, James R Downing, Charles G Mullighan, Stanley Pounds, M Madan Babu, Jinghui Zhang, Jeffrey E Rubnitz, Soheil Meshinchi, Xiaotu Ma, Jeffery M Klco.
      The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in UBTF in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with co-occurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. Additionally, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0160
  7. EMBO Rep. 2022 Feb 14. e52904
    Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody.
    Denis Tvorogov, Chloe A L Thompson-Peach, Johannes Foßelteder, Mara Dottore, Frank Stomski, Suraiya A Onnesha, Kelly Lim, Paul A B Moretti, Stuart M Pitson, David M Ross, Andreas Reinisch, Daniel Thomas, Angel F Lopez.
      Calreticulin (CALR) is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches. We developed a specific rat monoclonal IgG2α antibody, 4D7, directed against the common sequence encoded by both insertion and deletion mutations. 4D7 selectively bound to cells co-expressing mutant CALR and thrombopoietin receptor (TpoR) and blocked JAK-STAT signalling, TPO-independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR. Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation. Together, our data demonstrate a novel therapeutic approach to target a problematic disease driven by a recurrent somatic mutation that would normally be considered undruggable.
    Keywords:  calreticulin; monoclonal antibody; myelofibrosis; myeloproliferative neoplasm; stem cell progenitor
    DOI:  https://doi.org/10.15252/embr.202152904
  8. J Clin Oncol. 2022 Feb 18. JCO2102188
    Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy.
    Claire N Harrison, Jacqueline S Garcia, Tim C P Somervaille, James M Foran, Srdan Verstovsek, Catriona Jamieson, Ruben Mesa, Ellen K Ritchie, Srinivas K Tantravahi, Pankit Vachhani, Casey L O'Connell, Rami S Komrokji, Jason Harb, Jessica E Hutti, Leanne Holes, Abdullah A Masud, Silpa Nuthalapati, Jalaja Potluri, Naveen Pemmaraju.
       PURPOSE: Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (NCT03222609).
    METHODS: Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety.
    RESULTS: High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%).
    CONCLUSION: The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.
    DOI:  https://doi.org/10.1200/JCO.21.02188
  9. Front Oncol. 2022 ;12 806137
    Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions.
    Long Su, Yuan-Yuan Shi, Zeng-Yan Liu, Su-Jun Gao.
      Mutations in CCAAT enhancer binding protein A gene (CEBPA) are one of the common genetic alterations in acute myeloid leukemia (AML). Recently, the emergence of new evidence makes it necessary to reconsider the subsets and treatment of AML patients with CEBPA mutations. This review will summarize the history of research progress of CEBPA mutations in AML, the heterogeneities of AML with CEBPA double mutations (CEBPA dm), and two special subtypes of CEBPA mutated AML. We will discuss the treatment of AML with CEBPA mutations as well, and finally propose a new algorithm for the treatment of these patients, including both familial and sporadic CEBPA mutated AML patients. This review may be beneficial for further investigation and optimizing clinical management of AML patients with CEBPA mutations.
    Keywords:  CEBPA mutations; acute myeloid leukemia; prognosis; subsets; treatment
    DOI:  https://doi.org/10.3389/fonc.2022.806137
  10. Exp Hematol. 2022 Feb 15. pii: S0301-472X(22)00070-4. [Epub ahead of print]
    Specific effects of somatic GATA2 zinc finger mutations on erythroid differentiation.
    Enric Redondo Monte, Georg Leubolt, Roland Windisch, Paul Kerbs, Sayantanee Dutta, Theresa Sippenauer, Rouzanna Istvánffy, Robert A J Oostendorp, Linping Chen-Wichmann, Tobias Herold, Monica Cusan, Gunnar Schotta, Christian Wichmann, Philipp A Greif.
      GATA2 Zinc-Finger (ZF) mutations are associated with distinct entities of myeloid malignancies. The specific distribution of these mutations points towards different mechanisms of leukemogenesis depending on the affected ZF domain. In this study, we compared recurring somatic mutations in ZF1 and ZF2. All tested ZF mutants disrupted DNA-binding in vitro. In transcription assays, co-expression of FOG1 counteracted GATA2-dependent transcriptional activation, while a variable response to FOG1-mediated repression was observed for individual GATA2 mutants. In primary murine bone marrow cells, GATA2 wild-type (WT) expression inhibited colony formation, while this effect was reduced for both mutants A318T (ZF1) and L359V (ZF2) with a shift towards granulopoiesis. In primary human CD34+ bone marrow cells and in the myeloid cell line K562, ectopic expression of GATA2 L359V but not A318T or G320D caused a block of erythroid differentiation accompanied by downregulation of GATA1, STAT5B and PLCG1. Our findings may explain the role of GATA2 L359V during the progression of chronic myeloid leukemia and the collaboration of GATA2 ZF1 alterations with CEBPA double mutations in erythroleukemia.
    Keywords:  Acute Myeloid Leukemia; Blast Crisis; Chronic Myeloid Leukemia; Differentiation; Erythroid; GATA2; Myeloid Neoplasia
    DOI:  https://doi.org/10.1016/j.exphem.2022.02.002
  11. Leukemia. 2022 Feb 17.
    Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML.
    Mika Caplan, Karli J Wittorf, Kasidy K Weber, Samantha A Swenson, Tyler J Gilbreath, R Willow Hynes-Smith, Catalina Amador, R Katherine Hyde, Shannon M Buckley.
      Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects of genomic alterations. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry in parallel with RNAseq analysis using AML mouse models. These combined results identified 34 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. Here we focus on mitochondrial electron transfer proteins ETFA and ETFB. Silencing of ETFA and ETFB led to increased mitochondrial activity, mitochondrial stress, and apoptosis in AML cells, but had little to no effect on normal human CD34+ cells. These studies identify a set of proteins that have not previously been associated with leukemia and may ultimately serve as potential targets for therapeutic manipulation to hinder AML progression and help contribute to our understanding of the disease.
    DOI:  https://doi.org/10.1038/s41375-022-01518-z
  12. Oncotarget. 2022 ;13 319-330
    ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.
    Benigno C Valdez, David Murray, Bin Yuan, Yago Nieto, Uday Popat, Borje S Andersson.
      The antineoplastic activity of pre-transplant regimens in hematopoietic stem cell transplantation (HSCT) is a critical factor for acute myeloid leukemia (AML) patients. There is an urgent need to identify novel approaches without jeopardizing patient safety. We hypothesized that combination of drugs with different mechanisms of action would provide better cytotoxicity. We, therefore, determined the synergistic cytotoxicity of various combinations of the alkylating agents busulfan (Bu) and 4-hydroperoxycyclophosphamide (4HC), the nucleoside analog fludarabine (Flu) and the BCL2 inhibitor ABT199/venetoclax in AML cells. [Bu+4HC] and [Bu+Flu] inhibited cell proliferation and activated apoptosis; addition of ABT199 to either combinations significantly increased these effects with combination indexes < 1. Apoptosis is suggested by cleavages of PARP1 and CASPASE 3, DNA fragmentation, increased reactive oxygen species, decreased mitochondrial membrane potential, and increased pro-apoptotic proteins in the cytoplasm. A similar enhancement of apoptosis was observed in patient-derived cell samples. ABT199/venetocalx upregulated anti-apoptotic MCL1 as a compensatory mechanism but addition of [Bu+4HC] or [Bu+Flu] negated this effect by CASPASE 3-mediated cleavage of MEK1/2 and its substrate MCL1. CASPASE 3 caused cleavage of pro-survival β-CATENIN, which likely contributed to the activation of stress signaling pathways involving SAPK/JNK and AMPK. The observed synergistic cytotoxicity was associated with an inhibition of pro-survival pathways involving STAT1, STAT5 and PI3K. These findings will be useful in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.
    Keywords:  ABT199/venetoclax; acute myeloid leukemia; busulfan; cyclophosphamide; fludarabine
    DOI:  https://doi.org/10.18632/oncotarget.28193
  13. Mol Cell. 2022 Feb 17. pii: S1097-2765(22)00057-0. [Epub ahead of print]82(4): 833-851.e11
    HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.
    Huacheng Luo, Ganqian Zhu, Melanie A Eshelman, Tsz Kan Fung, Qian Lai, Fei Wang, Bernd B Zeisig, Julia Lesperance, Xiaoyan Ma, Shi Chen, Nicholas Cesari, Christopher Cogle, Baoan Chen, Bing Xu, Feng-Chun Yang, Chi Wai Eric So, Yi Qiu, Mingjiang Xu, Suming Huang.
      HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops. HOTTIP-mediated R-loops reinforce the CTCF boundary and facilitate formation of TADs to drive gene transcription. Either deleting CBS or targeting RNase H to eliminate R-loops in the boundary CBS of β-catenin TAD impaired CTCF boundary activity, inhibited promoter/enhancer interactions, reduced β-catenin target expression, and mitigated leukemogenesis in xenograft mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and leukemia development.
    Keywords:  AML leukemogenesis; CTCF chromatin boundary; HOTTIP lncRNA; R-loops; TAD formation; canonical Wnt transcription; cohesin complex; enhancer/promoter interactions
    DOI:  https://doi.org/10.1016/j.molcel.2022.01.014
  14. Br J Haematol. 2022 Feb 16.
    Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.
    Sandy On, Carolyn G Rath, Michelle Lan, Bobby Wu, Kimberly M Lau, Edna Cheung, William Alegria, Rebecca Young, Marisela Tan, Carrie Kim, Jennifer Phun, Nimish Patel, Gabriel Mannis, Aaron C Logan, Vanessa Kennedy, Aaron Goodman, Randy A Taplitz, Patricia A Young, Raymond Wen, Ila M Saunders.
      We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.
    Keywords:  acute myeloid leukaemia; fungal infections; hypomethylating agent; infectious complications; venetoclax
    DOI:  https://doi.org/10.1111/bjh.18051
  15. Life Sci. 2022 Feb 14. pii: S0024-3205(22)00102-3. [Epub ahead of print]295 120402
    Telomerase inhibition on acute myeloid leukemia stem cell induced apoptosis with both intrinsic and extrinsic pathways.
    Ali Rafat, Khadijeh Dizaji Asl, Zeinab Mazloumi, Ali Akbar Movassaghpour, Mehdi Talebi, Dariush Shanehbandi, Raheleh Farahzadi, Babak Nejati, Hojjatollah Nozad Charoudeh.
       AIMS: Acute Myeloid Leukemia (AML) is an invasive and lethal blood cancer caused by a rare population of Leukemia Stem Cells (LSCs). Telomerase activation is a limitless self-renewal process in LSCs. Apart from telomerase role in telomere lengthening, telomerase (especially hTERT subunit) inhibits intrinsic-, extrinsic-, and p53- mediated apoptosis pathways. In this study, the effect of Telomerase Inhibition (TI) on intrinsic-, extrinsic-, p53-mediated apoptosis, and DNMT3a and TET epigenetic markers in stem (CD34+) and differentiated (CD34-) AML cells is evaluated.
    MAIN METHODS: High-purity CD34+ (primary AML and KG-1a) cells were enriched using the Magnetic-Activated Cell Sorting (MACS) system. CD34+ and CD34- (primary AML and KG-1a) cells were treated with BIBR1532 and then, MTT assay, Annexin V/7AAD, Ki-67 assay, Telomere Length (TL) measurement, and transcriptional alterations of p53, hTERT, TET2, DNMT3a were analyzed. Finally, apoptosis-related genes and proteins were studied.
    KEY FINDINGS: TI with the IC50 values of 83.5, 33.2, 54.3, and 24.6 μM in CD34+ and CD34- (primary AML and KG-1a) cells significantly inhibited cell proliferation and induced apoptosis. However, TI had no significant effect on TL. The results also suggested TI induced intrinsic-, extrinsic-, and p53-mediated apoptosis. It was shown that the expression levels of DNMT3a and TET2 epigenetic markers were highly increased following TI.
    SIGNIFICANCE: In total, it was revealed that TI induced apoptosis through intrinsic, extrinsic, and p53 pathways and increased the expression of DNMT3a and TET2 epigenetic markers.
    Keywords:  AML; Apoptosis; Epigenetic markers; Telomerase; Telomerase activity
    DOI:  https://doi.org/10.1016/j.lfs.2022.120402
  16. Nat Cell Biol. 2022 Feb;24(2): 148-154
    Metabolic determination of cell fate through selective inheritance of mitochondria.
    Julia Döhla, Emilia Kuuluvainen, Nadja Gebert, Ana Amaral, Johanna I Englund, Swetha Gopalakrishnan, Svetlana Konovalova, Anni I Nieminen, Ella S Salminen, Rubén Torregrosa Muñumer, Kati Ahlqvist, Yang Yang, Hien Bui, Timo Otonkoski, Reijo Käkelä, Ville Hietakangas, Henna Tyynismaa, Alessandro Ori, Pekka Katajisto.
      Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions1-4. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
    DOI:  https://doi.org/10.1038/s41556-021-00837-0
  17. Cell Rep. 2022 02 15. pii: S2211-1247(22)00090-0. [Epub ahead of print]38(7): 110369
    DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding.
    Cathy J Spangler, Satya P Yadav, Dongxu Li, Carinne N Geil, Charlotte B Smith, Gang Greg Wang, Tae-Hee Lee, Robert K McGinty.
      DOT1L methylates histone H3 lysine 79 during transcriptional elongation and is stimulated by ubiquitylation of histone H2B lysine 120 (H2BK120ub) in a classical trans-histone crosstalk pathway. Aberrant genomic localization of DOT1L is implicated in mixed lineage leukemia (MLL)-rearranged leukemias, an aggressive subset of leukemias that lacks effective targeted treatments. Despite recent atomic structures of DOT1L in complex with H2BK120ub nucleosomes, fundamental questions remain as to how DOT1L-ubiquitin and DOT1L-nucleosome acidic patch interactions observed in these structures contribute to nucleosome binding and methylation by DOT1L. Here, we combine bulk and single-molecule biophysical measurements with cancer cell biology to show that ubiquitin and cofactor binding drive conformational changes to stimulate DOT1L activity. Using structure-guided mutations, we demonstrate that ubiquitin and nucleosome acidic patch binding by DOT1L are required for cell proliferation in the MV4; 11 leukemia model, providing proof of principle for MLL targeted therapeutic strategies.
    Keywords:  DOT1L; MLL-rearranged leukemia; chromatin; histone; lysine methyltransferase; mixed lineage leukemia (MLL); nucleosome; single-molecule FRET
    DOI:  https://doi.org/10.1016/j.celrep.2022.110369
  18. Haematologica. 2022 Feb 17.
    The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias.
    Rosa Paolillo, Mathias Boulanger, Pierre Gâtel, Ludovic Gabellier, Marion De Toledo, Denis Tempé, Rawan Hallal, Dana Akl, Jérôme Moreaux, Hayeon Baik, Elise Gueret, Christian Recher, Jean-Emmanuel Sarry, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis.
      Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase expression and ROS production, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. Gp91phox (CYBB-encoded Nox2 catalytic sub-unit), was found more expressed and active in leukemic cells from the FAB M4/M5 subtypes patients compared to FAB M0-M2 ones. Moreover, its expression was increased at the surface of patient's chemotherapy resistant AML cells. Using a gene expression-based score we finally demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis in AML patients. The prognosis NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.
    DOI:  https://doi.org/10.3324/haematol.2021.279889
  19. Sci Adv. 2022 Feb 18. 8(7): eabl8952
    The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia.
    Theodoros Karantanos, Patric Teodorescu, Brandy Perkins, Ilias Christodoulou, Christopher Esteb, Ravi Varadhan, Eric Helmenstine, Trivikram Rajkhowa, Bogdan C Paun, Challice Bonifant, W Brian Dalton, Lukasz P Gondek, Alison R Moliterno, Mark J Levis, Gabriel Ghiaur, Richard J Jones.
      The identification of new pathways supporting the myelodysplastic syndrome (MDS) primitive cells growth is required to develop targeted therapies. Within myeloid malignancies, men have worse outcomes than women, suggesting male sex hormone-driven effects in malignant hematopoiesis. Androgen receptor promotes the expression of five granulocyte colony-stimulating factor receptor-regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor regulating cytokine signaling in granulocytes, but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is up-regulated in primitive cells from patients with MDS and secondary acute myeloid leukemia (sAML). CCRL2 knockdown suppressed MDS92 and MDS-L cell growth and clonogenicity in vitro and in vivo and decreased JAK2/STAT3/STAT5 phosphorylation. CCRL2 coprecipitated with JAK2 and potentiated JAK2-STAT interaction. Erythroleukemia cells expressing JAK2V617F showed less effect of CCRL2 knockdown, whereas fedratinib potentiated the CCRL2 knockdown effect. Conclusively, our results implicate CCRL2 as an MDS/sAML cell growth mediator, partially through JAK2/STAT signaling.
    DOI:  https://doi.org/10.1126/sciadv.abl8952
  20. Blood. 2022 Feb 15. pii: blood.2021014309. [Epub ahead of print]
    Guiding the Global Evolution of Cytogenetic Testing for Hematologic Malignancies.
    Yassmine M N Akkari, Linda B Baughn, Adrian M Dubuc, Adam C Smith, Mar Mallo, Paola Dal Cin, María Díez-Campelo, Marta S Gallego, Isabel Granada, Detlef Thomas Haase, Brigitte Schlegelberger, Irma Slavutsky, Cristina Mecucci, Ross L Levine, Robert P Hasserjian, Francesc Sole, Brynn Levy, Xinjie Xu.
      Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies, and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, technical, and economic implications, we provide points to consider for the global evolution of cytogenetic testing.
    DOI:  https://doi.org/10.1182/blood.2021014309
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