bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–12–05
twenty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance).
  2. Targeting the cluster of differentiation 47/signal-regulatory protein alpha axis in myeloid malignancies.
  3. KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs.
  4. Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia.
  5. Acute myeloid leukemia cell membrane-coated nanoparticles for cancer vaccination immunotherapy.
  6. Isocitrate dehydrogenase mutations are associated with altered IL-1β responses in acute myeloid leukemia.
  7. The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements.
  8. Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.
  9. CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.
  10. HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort.
  11. Molecular characterization of the histone acetyltransferase CREBBP/EP300 genes in myeloid neoplasia.
  12. A phase I study of the fully human, fragment crystallizable-engineered, anti-CD-33 monoclonal antibody BI 836858 in patients with previously-treated acute myeloid leukemia.
  13. Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia.
  14. LNK (SH2B3) Inhibition Expands Healthy and Fanconi Anemia Human Hematopoietic Stem and Progenitor Cells.
  15. Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML.
  16. A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.
  17. Coordinated mis-splicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.
  18. Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.
  19. Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease.
  20. Influence of Telomere Length on the Achievement of Deep Molecular Response With Imatinib in Chronic Myeloid Leukemia Patients.
  21. Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia.
  1. Blood Adv. 2021 Nov 30. pii: bloodadvances.2021006242. [Epub ahead of print]
    Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance).
    Sydney Fobare, Jessica Kohlschmidt, Hatice Gulcin Ozer, Krzysztof Mrózek, Deedra Nicolet, Alice S Mims, Ramiro Garzon, James S Blachly, Shelley Orwick, Andrew J Carroll, Richard M Stone, Eunice S Wang, Jonathan E Kolitz, Bayard L Powell, Christopher C Oakes, Ann-Kathrin Eisfeld, Erin Hertlein, John C Byrd.
      Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006242
  2. Curr Opin Hematol. 2022 Jan 01. 29(1): 44-52
    Targeting the cluster of differentiation 47/signal-regulatory protein alpha axis in myeloid malignancies.
    Chen Wang, David A Sallman.
       PURPOSE OF REVIEW: The antitumor activity of macrophages is regulated by a balance of prophagocytic and antiphagocytic signals. Cluster of differentiation 47 (CD47), the dominant macrophage immune checkpoint ('do not eat me' signal), interacts with its receptor signal-regulatory protein alpha (SIRPα) to suppress phagocytic activities. This axis plays a pivotal role in immune evasion in myeloid malignancies as well as multiple cancers providing strong rationale for therapeutic exploitation.
    RECENT FINDINGS: Preclinical studies have revealed overexpression of CD47 on leukemic stem cells and myeloblasts from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which contributes to immune surveillance evasion and is associated with poor outcomes. Blockade of CD47 with different approaches has demonstrated proof-of-concept antitumor activities mainly through phagocytic clearance. Early phase clinical trials combining the anti-CD47 mAb magrolimab with the hypomethylating agent azacitidine have showed synergistic activities, deep and durable responses, as well as a tolerable safety profile in these patients, including those with TP53 mutations.
    SUMMARY: Targeting CD47/SIRPα axis, in combination with other therapeutic agents, represents a promising treatment approach for patients with myeloid malignancies, particularly the challenging TP53-mutated subgroup.
    DOI:  https://doi.org/10.1097/MOH.0000000000000691
  3. Cancer Discov. 2021 Dec 01. pii: candisc.1459.2020. [Epub ahead of print]
    KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs.
    Fangxue Yan, Jinyang Li, Jelena Milosevic, Ricardo Petroni, Suying Liu, Zhennan Shi, Salina Yuan, Janice M Reynaga, Yuwei Qi, Joshua Rico, Sixiang Yu, Yiman Liu, Susumu Rokudai, Neil Palmisiano, Sara E Meyer, Pamela J Sung, Liling Wan, Fei Lan, Benjamin A Garcia, Ben Z Stanger, David B Sykes, M Andres Blanco.
      Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene expression programs. We show that KAT6A is the initiator of a newly-described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyllysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small molecule inhibitors could be of high therapeutic interest for mono or combinatorial differentiation-based treatment of AML.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1459
  4. Sci Rep. 2021 Dec 02. 11(1): 23280
    Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia.
    Justine Klosner, Konstantin Agelopoulos, Christian Rohde, Stefanie Göllner, Christoph Schliemann, Wolfgang E Berdel, Carsten Müller-Tidow.
      Treatment of acute myeloid leukemia (AML) remains challenging and novel targets and synergistic therapies still need to be discovered. We performed a high-throughput RNAi screen in three different AML cell lines and primary human leukemic blasts to identify genes that synergize with common antileukemic therapies. We used a pooled shRNA library that covered 5043 different genes and combined transfection with exposure to either azacytidine or cytarabine analog to the concept of synthetic lethality. Suppression of the chemokine CXCL12 ranked highly among the candidates of the cytarabine group. Azacytidine in combination with suppression of genes within the neddylation pathway led to synergistic results. NEDD8 and RBX1 inhibition by the small molecule inhibitor pevonedistat inhibited leukemia cell growth. These findings establish an in vitro synergism between NEDD8 inhibition and azacytidine in AML. Taken together, neddylation constitutes a suitable target pathway for azacytidine combination strategies.
    DOI:  https://doi.org/10.1038/s41598-021-02695-0
  5. Leukemia. 2021 Nov 29.
    Acute myeloid leukemia cell membrane-coated nanoparticles for cancer vaccination immunotherapy.
    Daniel T Johnson, Jiarong Zhou, Ashley V Kroll, Ronnie H Fang, Ming Yan, Crystal Xiao, Xiufen Chen, Justin Kline, Liangfang Zhang, Dong-Er Zhang.
      Cancer vaccines are promising treatments to prevent relapse after chemotherapy in acute myeloid leukemia (AML) patients, particularly for those who cannot tolerate intensive consolidation therapies. Here, we report the development of an AML cell membrane-coated nanoparticle (AMCNP) vaccine platform, in which immune-stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. This AMCNP vaccination strategy stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. To demonstrate that this AMCNP vaccine enhances leukemia-specific antigen presentation and T cell responses, we modified a murine AML cell line to express membrane-bound chicken ovalbumin as a model antigen. AMCNPs were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulated antigen cross-presentation. Vaccination with AMCNPs significantly enhanced antigen-specific T cell expansion and effector function compared with control vaccines. Prophylactic vaccination with AMCNPs enhanced cellular immunity and protected against AML challenge. Moreover, in an AML post-remission vaccination model, AMCNP vaccination significantly enhanced survival in comparison to vaccination with whole leukemia cell lysates. Collectively, AMCNPs retained AML-specific antigens, elicited enhanced antigen-specific immune responses, and provided therapeutic benefit against AML challenge.
    DOI:  https://doi.org/10.1038/s41375-021-01432-w
  6. Leukemia. 2021 Dec 02.
    Isocitrate dehydrogenase mutations are associated with altered IL-1β responses in acute myeloid leukemia.
    Kathryn I Sunthankar, Matthew T Jenkins, Candace H Cote, Sweta B Patel, Robert S Welner, P Brent Ferrell.
      Mutations in isocitrate dehydrogenase 2 (IDH2) have been noted to impact cellular differentiation in addition to DNA and histone methylation. However, little is known about the impact of IDH2 mutations on intracellular signaling. Using an isogenic cell line model, we investigated both differentiation and signaling responses in IDH2 mutant cells and show augmented responses to inflammatory immune ligands. Using phospho-specific flow and mass cytometry, we demonstrate IDH2 mutant cells were significantly more sensitive to IL-1β at multiple downstream readouts. Further, bulk RNA sequencing confirmed increases in cytokine-related signaling pathways and NF-κB target genes. Single-cell RNA sequencing of unstimulated and stimulated cells confirmed altered IL-1β transcriptional responses in the IDH2 mutant cells. Targeted inhibition of the IKK complex reduced IL-1β responses and induced cell death in primary IDH-mutated leukemia samples. Together, these results confirm altered IL-1β signaling in IDH2 mutant cells and identify this pathway as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41375-021-01487-9
  7. Haematologica. 2021 Dec 02.
    The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements.
    Sarah Grasedieck, Ariene Cabantog, Liam MacPhee, Junbum Im, Christoph Ruess, Burcu Demir, Nadine Sperb, Frank G Rücker, Konstanze Döhner, Tobias Herold, Jonathan R Pollack, Lars Bullinger, Arefeh Rouhi, Florian Kuchenbauer.
      Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary patient samples as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chr3 abnormalities. Furthermore, we show that NRIP1 knockdown negatively affects the proliferation and survival of 3q-rearranged AML cells and increases their sensitivity towards ATRA, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.
    DOI:  https://doi.org/10.3324/haematol.2021.276048
  8. Proc Natl Acad Sci U S A. 2021 Dec 07. pii: e2116427118. [Epub ahead of print]118(49):
    Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.
    Francesca Ferraro, Christopher A Miller, Keegan A Christensen, Nichole M Helton, Margaret O'Laughlin, Catrina C Fronick, Robert S Fulton, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Clara D Bloomfield, Sai Mukund Ramakrishnan, Ryan B Day, Lukas D Wartman, Geoffrey L Uy, John S Welch, Matthew J Christopher, Sharon E Heath, Jack D Baty, Matthew J Schuelke, Jacqueline E Payton, David H Spencer, Michael P Rettig, Daniel C Link, Matthew J Walter, Peter Westervelt, John F DiPersio, Timothy J Ley.
      Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.
    Keywords:  acute myeloid leukemia; cancer genomics; checkpoints; chemotherapy; immunosuppression
    DOI:  https://doi.org/10.1073/pnas.2116427118
  9. J Clin Oncol. 2021 Dec 02. JCO2101595
    CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.
    Adam J Lamble, Lisa Eidenschink Brodersen, Todd A Alonzo, Jim Wang, Laura Pardo, Lillian Sung, Todd M Cooper, E Anders Kolb, Richard Aplenc, Sarah K Tasian, Michael R Loken, Soheil Meshinchi.
       PURPOSE: Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).
    MATERIALS AND METHODS: AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.
    RESULTS: The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations (P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations (P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.
    CONCLUSION: CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.
    DOI:  https://doi.org/10.1200/JCO.21.01595
  10. Oncogene. 2021 Dec 02.
    HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort.
    Elyse C Page, Susan L Heatley, Laura N Eadie, Barbara J McClure, Charles E de Bock, Sofia Omari, David T Yeung, Timothy P Hughes, Paul Q Thomas, Deborah L White.
      The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2r DS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1 loss of function on the leukemic burden. We demonstrated HMGN1 KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1 overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2 and HMGN1 co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2r DS-ALL and identify HMGN1 as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.
    DOI:  https://doi.org/10.1038/s41388-021-02126-4
  11. Leukemia. 2021 Nov 29.
    Molecular characterization of the histone acetyltransferase CREBBP/EP300 genes in myeloid neoplasia.
    Sunisa Kongkiatkamon, Simona Pagliuca, Vera Adema, Yasunobu Nagata, Cassandra M Kerr, Wencke Walter, Hassan Awada, Stephan Hutter, Carmelo Gurnari, Heesun J Rogers, Manja Meggendorfer, Yogen Saunthararajah, Torsten Haferlach, Valeria Visconte, Jaroslaw P Maciejewski.
      
    DOI:  https://doi.org/10.1038/s41375-021-01479-9
  12. Haematologica. 2021 Dec 02.
    A phase I study of the fully human, fragment crystallizable-engineered, anti-CD-33 monoclonal antibody BI 836858 in patients with previously-treated acute myeloid leukemia.
    Sumithira Vasu, Jessica K Altman, Geoffrey L Uy, Martin S Tallman, Ivana Gojo, Gerard Lozanski, Ute Burkard, Annika Osswald, Pamela James, Björn Rüter, William Blum.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2020.274118
  13. Blood Adv. 2021 Nov 30. pii: bloodadvances.2021004926. [Epub ahead of print]
    Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia.
    Sabrin Tahri, Tarek H Mouhieddine, Robert A Redd, Luisa M Lampe, Katarina I Nilsson, Habib El-Khoury, Nang Kham Su, Amin H Nassar, Elio Adib, Govind Bindra, Sarah Abou Alaiwi, Lorenzo Trippa, David P Steensma, Jorge Castillo, Steven P Treon, Irene M Ghobrial, Adam S Sperling.
      Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström macroglobulinemia (WM) and its association with clinical outcomes. In order to unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2 or ASXL1 (DTA) and was detected in 14% of 587 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM) or WM. The presence and size of DTA clones was associated with older age. Patients with CH had an increased risk of progression from MGUS or SWM to WM but not worse overall survival in this cohort. These findings further illuminate the clinical effects of CH in patients with indolent NHL such as WM.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004926
  14. Blood Adv. 2021 Nov 29. pii: bloodadvances.2021004205. [Epub ahead of print]
    LNK (SH2B3) Inhibition Expands Healthy and Fanconi Anemia Human Hematopoietic Stem and Progenitor Cells.
    Nicholas Holdreith, Grace Y Lee, Vemika Chandra, Carlo Salas Salinas, Peter Nicholas, Timothy S Olson, Wei Tong.
      Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for a variety of hematological diseases. Allogenic HSCT requires hematopoietic stem cells (HSCs) from matched donors and comes with cytotoxicity and mortality. Recent advances in genome modification of HSCs have demonstrated the possibility of using autologous HSCT-based gene therapy to cure monogenic diseases, such as the inherited bone marrow failure (BMF) syndrome Fanconi Anemia (FA). However, for FA and other BMF syndromes insufficient HSC numbers with functional defects results in delayed hematopoietic recovery and increased risk of graft failure. We and others previously identified the adaptor protein Lnk (Sh2b3) as a critical negative regulator of murine HSC homeostasis. However, whether LNK (SH2B3) controls human HSCs has not been studied. Here, we demonstrate that depletion of LNK via lentiviral expression of miR30-based short hairpin RNAs (shRNAs) resulted in robust expansion of transplantable human HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Importantly, LNK depletion enhanced cytokine mediated JAK/STAT activation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that LNK depletion expands primary HSPCs associated with FA. In xenotransplant, engraftment defects of FANCD2-depleted FA-like HSCs were markedly improved by LNK inhibition. Finally, targeting LNK in primary bone marrow HSPCs from FA patients enhanced their colony forming potential in vitro. Together, these results demonstrate the potential of targeting LNK to expand HSCs to improve HSCT and HSCT-based gene therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004205
  15. Oncogene. 2021 Dec 03.
    Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML.
    Luciano Nicosia, Francesca Ludovica Boffo, Elena Ceccacci, Fabio Conforti, Isabella Pallavicini, Fabio Bedin, Roberto Ravasio, Enrico Massignani, Tim C P Somervaille, Saverio Minucci, Tiziana Bonaldi.
      The histone demethylase LSD1 is over-expressed in hematological tumors and has emerged as a promising target for anticancer treatment, so that several LSD1 inhibitors are under development and testing, in preclinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unraveled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the downregulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viability in vitro and of tumor growth in vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine-signaling pathways are upregulated by LSD1 inhibitors through GSE1-protein reduction and that LSD1 and GSE1 colocalize at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights into GSE1 as a novel therapeutic target for AML.
    DOI:  https://doi.org/10.1038/s41388-021-02123-7
  16. Leuk Res. 2021 Nov 11. pii: S0145-2126(21)01750-1. [Epub ahead of print]112 106749
    A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.
    Jane L Liesveld, Andrea Baran, Mitra Azadniv, Haley Misch, Katherine Nedrow, Michael Becker, Kah Poh Loh, Kristen M O'Dwyer, Jason H Mendler.
      A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.
    Keywords:  AML; Elderly; Relapsed/refractory; mTOR inhibition
    DOI:  https://doi.org/10.1016/j.leukres.2021.106749
  17. Blood. 2021 Dec 03. pii: blood.2021012652. [Epub ahead of print]
    Coordinated mis-splicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.
    Courtnee A Clough, Joseph Pangallo, Martina Sarchi, Janine O Ilagan, Khrystyna North, Rochelle Bergantinos, Massiel Chavez Stolla, Jasmine Naru, Patrick Nugent, Eunhee Kim, Derek L Stirewalt, Arvind R Subramaniam, Omar Abdel-Wahab, Janis L Abkowitz, Robert K Bradley, Sergei Doulatov.
      SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts, a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause ring sideroblasts (RS) remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell (iPSC) model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces mis-splicing of ~100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All three mis-splicing events reduce protein expression, notably occurring via 5' UTR alteration and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated mis-splicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing ring sideroblast formation.
    DOI:  https://doi.org/10.1182/blood.2021012652
  18. Cancer Discov. 2021 Dec 03. pii: candisc.0522.2021. [Epub ahead of print]
    Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.
    Sylvain Garciaz, Andrew A Guirguis, Sebastian Muller, Fiona C Brown, Yih-Chih Chan, Ali Motazedian, Caitlin L Rowe, James A Kuzich, Kah Lok Chan, Kevin Tran, Lorey Smith, Laura MacPherson, Brian Liddicoat, Enid Y N Lam, Tatiana Caneque, Marian L Burr, Veronique Litalien, Giovanna Pomilio, Mathilde Poplineau, Estelle Duprez, Sarah-Jane Dawson, Georg Ramm, Andrew G Cox, Kristin K Brown, David C S Huang, Andrew H Wei, Kate McArthur, Raphael Rodriguez, Mark A Dawson.
      Cancer cell metabolism is increasingly recognised as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small molecule ironomycin (AM5) reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent non-redundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0522
  19. Blood. 2021 Sep 10. pii: blood.2021013531. [Epub ahead of print]
    Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease.
    Peter Miller, Dandi Qiao, Joselyn Rojas-Quintero, Michael C Honigberg, Adam S Sperling, Christopher J Gibson, Alexander G Bick, Abhishek Niroula, Marie E McConkey, Brittany Sandoval, Brian Miller, Weiwei Shi, Kaushik Viswanathan, Matthew Joseph Leventhal, Lillian Werner, Matthew Moll, Brian Cade, R Graham Barr, Adolfo Correa, L Adrienne Cupples, Sina A Gharib, Deepti Jain, Stephanie Gogarten, Leslie Lange, Stephanie London, Ani Manichaikul, George O'Connor, Elizabeth Oelsner, Susan Redline, Stephen S Rich, Jerome I Rotter, Vasan Ramachandran, Bing Yu, Lynette M Sholl, Donna Neuberg, Siddhartha Jaiswal, Bruce Levy, Caroline Owen, Pradeep Natarajan, Edwin K Silverman, Peter van Galen, Yohannes Tesfaigzi, Michael Cho, Benjamin L Ebert.
      Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 had moderate-to-very-severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -5.7%; adjusted 95% CI, -8.8 to -2.6), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
    DOI:  https://doi.org/10.1182/blood.2021013531
  20. Hemasphere. 2021 Dec;5(12): e657
    Influence of Telomere Length on the Achievement of Deep Molecular Response With Imatinib in Chronic Myeloid Leukemia Patients.
    Natalia Estrada, Blanca Xicoy, Fabian Beier, Olga Garcia, Cristian Morales, Concepción Boqué, Miguel Sagüés, Mónica S Ventura Ferreira, Rolando Vallansot, Sílvia Marcé, Marta Cabezón, Tim H Brümmendorf, Lurdes Zamora.
      Tyrosine kinase inhibitors have dramatically changed the outcome of chronic myeloid leukemia (CML), and nowadays, one of the main treatment goals is the achievement of deep molecular responses (DMRs), which can eventually lead to therapy discontinuation approaches. Few biological factors at diagnosis have been associated with this level of response. Telomere length (TL) in peripheral blood cells of patients with CML has been related to disease stage, response to therapy and disease progression, but little is known about its role on DMR. In this study, we analyzed if age-adjusted TL (referred as "delta-TL") at diagnosis of chronic phase (CP)-CML might correlate with the achievement of DMR under first-line imatinib treatment. TL from 96 CP-CML patients had been retrospectively analyzed at diagnosis by monochrome multiplex quantitative PCR. We observed that patients with longer age-adjusted telomeres at diagnosis had higher probabilities to achieve DMR with imatinib than those with shortened telomeres (P = 0.035 when delta-TL was studied as a continuous variable and P = 0.047 when categorized by the median). Moreover, patients carrying long telomeres also achieved major molecular response significantly earlier (P = 0.012). This study provides proof of concept that TL has a role in CML biology and when measured at diagnosis of CP-CML could help to identify patients likely to achieve DMR to first-line imatinib treatment.
    DOI:  https://doi.org/10.1097/HS9.0000000000000657
  21. Clin Cancer Res. 2021 Dec 03. pii: clincanres.1295.2021. [Epub ahead of print]
    Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia.
    Eytan M Stein, Daniel J DeAngelo, Jörg Chromik, Manik Chatterjee, Sebastian Bauer, Chia-Chi Lin, Cristina Suarez, Filip De Vos, Neeltje Steeghs, Phillippe A Cassier, David Tai, Jean-Jacques Kiladjian, Noboru Yamamoto, Rogier Mous, Jordi Esteve, Hironobu Minami, Stéphane Ferretti, Nelson Guerreiro, Christophe Meille, Rajkumar Radhakrishnan, Bernard Pereira, Luisa Mariconti, Ensar Halilovic, Claire Fabre, Cecilia Carpio.
       PURPOSE: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers.
    EXPERIMENTAL DESIGN: Initial dosing regimens were: 1A (Day 1; 21-day cycle; dose 12.5-350 mg); 2A (Days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (Days 1 and 8; 28-day cycle) and 2C (Days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLTs) during Cycle 1.
    RESULTS: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced Grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% (95% CI, 2.2-27.4) in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), or 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively.
    CONCLUSIONS: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1295
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