bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–07–18
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells.
  2. Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.
  3. Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).
  4. Author Correction: SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia.
  5. A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication.
  6. Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis.
  7. Glutamate-cysteine ligase catalytic subunit as a therapeutic target in acute myeloid leukemia and solid tumors.
  8. Novel METTL3 Modulators for Treating Acute Myeloid Leukemia (AML).
  9. Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.
  10. Measurable residual disease of canonical versus non-canonical DNMT3A, TET2, or ASXL1 mutations in AML at stem cell transplantation.
  11. Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system.
  12. Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development.
  13. TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling.
  14. Mapping the cellular origin and early evolution of leukemia in Down syndrome.
  15. Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia.
  16. Relationship between clone metrics and clinical outcome in clonal cytopenia.
  17. Diagnostic Challenge and Clinical Dilemma: The Long Reach of Clonal Hematopoiesis.
  18. Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner.
  19. Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia.
  20. Several Types of Mutations Contribute to the Landscape of Clonal Hematopoiesis.
  21. Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT.
  22. Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.
  23. Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia.
  24. Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia.
  25. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML.
  26. A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.
  1. Hemasphere. 2021 Aug;5(8): e610
    The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells.
    Noortje van Gils, Tania Martiañez Canales, Eline Vermue, Arjo Rutten, Fedor Denkers, Tiem van der Deure, Gert J Ossenkoppele, Francis Giles, Linda Smit.
      Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.
    DOI:  https://doi.org/10.1097/HS9.0000000000000610
  2. Cancer. 2021 Jul 13.
    Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.
    Kunhwa Kim, Abhishek Maiti, Sanam Loghavi, Rasoul Pourebrahim, Tapan M Kadia, Caitlin R Rausch, Ken Furudate, Naval G Daver, Yesid Alvarado, Maro Ohanian, Koji Sasaki, Nicholas J Short, Koichi Takahashi, Musa Yilmaz, Guilin Tang, Farhad Ravandi, Hagop M Kantarjian, Courtney D DiNardo, Marina Y Konopleva.
       BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).
    METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.
    RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.
    CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.
    Keywords:  TP53; acute myeloid leukemia (AML); decitabine; outcome; venetoclax
    DOI:  https://doi.org/10.1002/cncr.33689
  3. Blood Adv. 2021 Jul 13. 5(13): 2775-2787
    Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).
    Alison R Walker, Guido Marcucci, Jun Yin, William Blum, Wendy Stock, Jessica Kohlschmidt, Krzysztof Mrózek, Andrew J Carroll, Ann-Kathrin Eisfeld, Eunice S Wang, Sawyer Jacobson, Jonathan E Kolitz, Mohan Thakuri, Grerk Sutamtewagul, Ravi Vij, Robert K Stuart, John C Byrd, Clara D Bloomfield, Richard M Stone, Richard A Larson.
      Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004233
  4. Leukemia. 2021 Jul 08.
    Author Correction: SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia.
    Inge van der Werf, Anna Wojtuszkiewicz, Huilan Yao, Rocco Sciarrillo, Manja Meggendorfer, Stephan Hutter, Wencke Walter, Jeroen Janssen, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, Gerrit Jansen, Gertjan J L Kaspers, Richard Groen, Gert Ossenkoppele, Jacqueline Cloos.
      
    DOI:  https://doi.org/10.1038/s41375-021-01340-z
  5. Blood. 2021 Jul 13. pii: blood.2021011707. [Epub ahead of print]
    A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication.
    Yue Sheng, Jiangbo Wei, Fang Yu, Huanzhou Xu, Chunjie Yu, Qiong Wu, Yin Liu, Lei Li, Xiao-Long Cui, Xueying Gu, Bin Shen, Wei Li, Yong Huang, Sumita Bhaduri-Mcintosh, Chuan He, Zhijian Qian.
      YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in Acute Myeloid Leukemia (AML) and that it is required for proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We find that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem/progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs, but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides the compelling evidence to show an oncogenic role and a distinct mechanism of YTHDC1 in AML.
    DOI:  https://doi.org/10.1182/blood.2021011707
  6. Cancer Discov. 2021 Jul;2(4): 319-325
    Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis.
    Laura W Dillon, Jack Ghannam, Chidera Nosiri, Gege Gui, Meghali Goswami, Katherine R Calvo, Katherine E Lindblad, Karolyn A Oetjen, Matthew Wilkerson, Anthony R Soltis, Gauthaman Sukumar, Clifton L Dalgard, Julie Thompson, Janet Valdez, Christin B DeStefano, Catherine Lai, Adam Sciambi, Robert Durruthy-Durruthy, Aaron Llanso, Saurabh Gulati, Shu Wang, Aik Ooi, Pradeep K Dagur, J Philip McCoy, Patrick Burr, Yuesheng Li, Christopher S Hourigan.
      Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML post-treatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here, that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing, and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody-oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A and TET2 mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.
    Keywords:  acute myeloid leukemia; clonal hematopoiesis; personalized medicine; proteogenomics; single-cell DNA sequencing
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0046
  7. Am J Cancer Res. 2021 ;11(6): 2911-2927
    Glutamate-cysteine ligase catalytic subunit as a therapeutic target in acute myeloid leukemia and solid tumors.
    Chiou-Hong Lin, John P Vu, Chen-Yen Yang, Mint Sirisawad, Chun-Te Chen, Hung Dao, Jing Liu, Xuan Ma, Chin Pan, Joseph Cefalu, Chris Tse, Erica Jackson, Hsu-Ping Kuo.
      Acute myeloid leukemia (AML) is a highly heterogenous and aggressive disease with a poor prognosis, necessitating further improvements in treatment therapies. Recently, several targeted therapies have become available for specific AML populations. To identify potential new therapeutic targets for AML, we analyzed published genome wide CRISPR-based screens to generate a gene essentiality dataset across a panel of 14 human AML cell lines while eliminating common essential genes through integration analysis with core fitness genes among 324 human cancer cell lines and DepMap databases. The key glutathione metabolic enzyme, glutamate-cysteine ligase catalytic subunit (GCLC), met the selection threshold. Using CRISPR knockout, GCLC was confirmed to be essential for the cell growth, survival, clonogenicity, and leukemogenesis in AML cells but was comparatively dispensable for normal hematopoietic stem and progenitor cells (HSPCs), indicating that GCLC is a potential therapeutic target for AML. In addition, we evaluated the essentiality of GCLC in solid tumors and demonstrated that GCLC represents a synthetic lethal target for ARID1A-deficient ovarian and gastric cancers.
    Keywords:  Acute myeloid leukemia (AML); CRISPR; glutamate-cysteine ligase catalytic subunit (GCLC); glutathione metabolic enzyme; synthetic lethality
  8. ACS Med Chem Lett. 2021 Jul 08. 12(7): 1061-1062
    Novel METTL3 Modulators for Treating Acute Myeloid Leukemia (AML).
    Ram W Sabnis.
      
    DOI:  https://doi.org/10.1021/acsmedchemlett.1c00280
  9. Haematologica. 2021 Jul 15.
    Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.
    Dimitrios Papaioannou, Hatice G Ozer, Deedra Nicolet, Amog P Urs, Tobias Herold, Krzysztof Mrózek, Aarif M N Batcha, Klaus H Metzeler, Ayse S Yilmaz, Stefano Volinia, Marius Bill, Jessica Kohlschmidt, Maciej Pietrzak, Christopher J Walker, Andrew J Carroll, Jan Braess, Bayard L Powell, Ann-Kathrin Eisfeld, Geoffrey L Uy, Eunice S Wang, Jonathan E Kolitz, Richard M Stone, Wolfgang Hiddemann, John C Byrd, Clara D Bloomfield, Ramiro Garzon.
      Expression levels of long non-coding RNAs (lncRNAs) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNAs in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged.
    DOI:  https://doi.org/10.3324/haematol.2021.266643
  10. Bone Marrow Transplant. 2021 Jul 15.
    Measurable residual disease of canonical versus non-canonical DNMT3A, TET2, or ASXL1 mutations in AML at stem cell transplantation.
    Madlen Jentzsch, Juliane Grimm, Marius Bill, Johannes Küpper, Donata Backhaus, Dominic Brauer, Julia Schulz, Georg-Nikolaus Franke, Vladan Vucinic, Dietger Niederwieser, Uwe Platzbecker, Sebastian Schwind.
      
    DOI:  https://doi.org/10.1038/s41409-021-01407-6
  11. Cancer Sci. 2021 Jul 12.
    Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system.
    Akihiko Yokoyama.
      Homeostasis of the hematopoietic system is achieved in a hierarchy, with hematopoietic stem cells at the pinnacle. Because only hematopoietic stem cells (HSCs) can self-renew, the size of the hematopoietic system is strictly controlled. In hematopoietic reconstitution experiments, one HSC can reconstitute the entire hematopoietic system, whereas 50 multipotent progenitors cannot. This indicates that only HSCs self-renew, whereas non-HSC hematopoietic progenitors are programmed to differentiate or senesce. Oncogenic mutations of the mixed lineage leukemia gene (MLL) overcome this "programmed differentiation" by conferring the self-renewing ability on non-HSC hematopoietic progenitors. In leukemia, mutated MLL proteins constitutively activate a broad range of previously transcribed CpG-rich promoters by an MLL-mediated transcriptional activation system. This system promotes self-renewal by replicating an expression profile similar to that of the mother cell in its daughter cells. In this transcriptional activation system, MLL binds to unmethylated CpG-rich promoters and recruits RNA polymerase II. MLL recruits p300/CBP through its transcriptional activation domain, which acetylates histone H3 at lysines 9, 18, and 27. The AF4 family/ENL family/P-TEFb complex (AEP) binds to acetylated H3K9/18/27 to activate transcription. Gene rearrangements of MLL with AEP- or CBP /p300-complex components generate constitutively active transcriptional machinery of this transcriptional activation system, which causes aberrant self-renewal of leukemia stem cells. Inhibitors of the components of this system effectively decrease their leukemogenic potential.
    Keywords:  Leukemia; molecular therapy; self-renewal; transcriptional machinery
    DOI:  https://doi.org/10.1111/cas.15054
  12. Exp Hematol Oncol. 2021 Jul 10. 10(1): 39
    Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development.
    Yiyi Yao, Fenglin Li, Jiansong Huang, Jie Jin, Huafeng Wang.
      Despite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC-BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.
    Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Environment-mediated drug resistance; Interaction; Leukemia stem cell
    DOI:  https://doi.org/10.1186/s40164-021-00233-2
  13. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00784-1. [Epub ahead of print]36(2): 109386
    TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling.
    Puneet Agarwal, Hui Li, Kwangmin Choi, Kathleen Hueneman, Jianbo He, Robert S Welner, Daniel T Starczynowski, Ravi Bhatia.
      Chronic myeloid leukemia (CML) is propagated by leukemia stem cells (LSCs) that are not eradicated by tyrosine kinase inhibitor (TKI) treatment and persist as a source of disease recurrence. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) and LSC maintenance. Using a murine CML model, we examine leukemia-induced alterations in mesenchymal cell populations. We show that 6C3+ stromal progenitors expand in CML BM and exhibit increased LSC but reduced HSC supportive capacity. Tumor necrosis factor alpha (TNF-α) signaling mediates expansion and higher expression of CXCL1 in CML BM 6C3+ cells and higher expression of the CXCL1 receptor CXCR2 in LSCs. CXCL1 enhances LSC proliferation and self-renewal, whereas CXCR2 inhibition reduces LSC growth and enhances LSC targeting in combination with tyrosine kinase inhibitors (TKIs). We find that TNF-α-mediated alterations in CML BM stromal niches enhance support of LSC maintenance and growth via CXCL1-CXCR2 signaling and that CXCR2 inhibition effectively depletes CML LSCs.
    Keywords:  6C3; CML; CXCL1; CXCR2; TNF-α; bone marrow microenvironment; inflammation; leukemic stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2021.109386
  14. Science. 2021 07 09. pii: eabf6202. [Epub ahead of print]373(6551):
    Mapping the cellular origin and early evolution of leukemia in Down syndrome.
    Elvin Wagenblast, Joana Araújo, Olga I Gan, Sarah K Cutting, Alex Murison, Gabriela Krivdova, Maria Azkanaz, Jessica L McLeod, Sabrina A Smith, Blaise A Gratton, Sajid A Marhon, Martino Gabra, Jessie J F Medeiros, Sanaz Manteghi, Jian Chen, Michelle Chan-Seng-Yue, Laura Garcia-Prat, Leonardo Salmena, Daniel D De Carvalho, Sagi Abelson, Mohamed Abdelhaleem, Karen Chong, Maian Roifman, Patrick Shannon, Jean C Y Wang, Johann K Hitzler, David Chitayat, John E Dick, Eric R Lechman.
      Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
    DOI:  https://doi.org/10.1126/science.abf6202
  15. Elife. 2021 Jul 15. pii: e64960. [Epub ahead of print]10
    Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia.
    William F Richter, Rohan N Shah, Alexander J Ruthenburg.
      MLL-rearranged leukemia depends on H3K79 methylation. Depletion of this transcriptionally-activating mark by DOT1L deletion or high concentrations of the inhibitor pinometostat downregulates HOXA9 and MEIS1, and consequently reduces leukemia survival. Yet some MLL-rearranged leukemias are inexplicably susceptible to low-dose pinometostat, far below concentrations that downregulate this canonical proliferation pathway. In this context, we define alternative proliferation pathways that more directly derive from H3K79me2 loss. By ICeChIP-seq, H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion targets, with paradoxical increases of H3K4me3 and loss of H3K27me3. Although downregulation of polycomb components accounts for some of the proliferation defect, transcriptional downregulation of FLT3 is the major pathway. Loss-of-FLT3-function recapitulates the cytotoxicity and gene expression consequences of low-dose pinometostat, whereas overexpression of constitutively active STAT5A, a target of FLT3-ITD-signalling, largely rescues these defects. This pathway also depends on MLL1, indicating combinations of DOT1L, MLL1 and FLT3 inhibitors should be explored for treating FLT3-mutant leukemia.
    Keywords:  cancer biology; chromosomes; gene expression; none
    DOI:  https://doi.org/10.7554/eLife.64960
  16. Blood. 2021 07 13. pii: blood.2021011323. [Epub ahead of print]
    Relationship between clone metrics and clinical outcome in clonal cytopenia.
    Anna Galli, Gabriele Todisco, Eulalia Catamo, Cinzia Sala, Chiara Elena, Sara Pozzi, Elisa Bono, Virginia V Ferretti, Ettore Rizzo, Elisabetta Molteni, Silvia Zibellini, Martina Sarchi, Emanuela Boveri, Jacqueline Ferrari, Nicolas Fiorelli, Clara Camaschella, Paolo Gasparini, Daniela Toniolo, Mario Cazzola, Luca Malcovati.
      Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that are associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n=355) or with unexplained anemia (n=177), and 592 patients with overt MN. Ninety-two of 311 (30%) ICUS patients carried a somatic genetic lesion that allowed diagnosis of CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of non-anemic and anemic community-dwelling individuals, respectively (P=.045). Different mutation patterns and variant allele frequencies (VAF) (clone metrics parameters) were observed in the conditions studied (P<.001). Recurrent mutation patterns exhibited different VAF values associated with marrow dysplasia (0.17-0.48, P<.001), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified two major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR=1.8, P<.001). Within CCUS patients, the 2 clusters had different risk of progression into MN (HR=2.7, P<.001). Within the MN-like cluster, distinct subsets with different risk of progression into MN (P<.001) could be identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes, and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical to inform clinical decision-making in patients with clonal cytopenia.
    DOI:  https://doi.org/10.1182/blood.2021011323
  17. Clin Chem. 2021 Jul 15. pii: hvab105. [Epub ahead of print]
    Diagnostic Challenge and Clinical Dilemma: The Long Reach of Clonal Hematopoiesis.
    Afaf Osman, Jay L Patel.
       BACKGROUND: Widespread application of massively parallel sequencing has resulted in recognition of clonal hematopoiesis in various clinical settings and on a relatively frequent basis. Somatic mutations occur in individuals with normal blood counts, and increase in frequency with age. The genes affected are the same genes that are commonly mutated in overt myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). This phenomenon is referred to as clonal hematopoiesis of indeterminate potential (CHIP).
    CONTENT: In this review, we explore the diagnostic and clinical implications of clonal hematopoiesis. In addition to CHIP, clonal hematopoiesis may be seen in patients with cytopenia who do not otherwise meet criteria for hematologic malignancy, a condition referred to as clonal cytopenia of undetermined significance (CCUS). Distinguishing CHIP and CCUS from overt myeloid neoplasm is a challenge to diagnosticians due to the overlapping mutational landscape observed in these conditions. We describe helpful laboratory and clinical features in making this distinction. CHIP confers a risk of progression to overt hematologic malignancy similar to other premalignant states. CHIP is also associated with a proinflammatory state with multisystem implications and increased mortality risk due to cardiovascular events. The current approach to follow up and management of patients with clonal hematopoiesis is described.
    SUMMARY: Nuanced understanding of clonal hematopoiesis is essential for diagnosis and clinical management of patients with hematologic conditions. Further data are needed to more accurately predict the natural history and guide management of these patients with respect to both malignant progression as well as nonhematologic sequelae.
    DOI:  https://doi.org/10.1093/clinchem/hvab105
  18. Cancer Lett. 2021 Jul 10. pii: S0304-3835(21)00337-2. [Epub ahead of print]520 132-142
    Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner.
    Maria V Yusenko, Abhiruchi Biyanee, Mattias K Andersson, Silke Radetzki, Jens P von Kries, Göran Stenman, Karl-Heinz Klempnauer.
      Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies. Here, we have used a MYB reporter cell line to screen a library of FDA-approved drugs for novel MYB inhibitors. We demonstrate that proteasome inhibitors have significant MYB-inhibitory activity, prompting us to characterize the proteasome inhibitor oprozomib in more detail. Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition.
    Keywords:  Adenoid cystic carcinoma; Inhibitor; MYB; Myeloid leukemia; Proteasome inhibitor
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.010
  19. Clin Cancer Res. 2021 Jul 12. pii: clincanres.0935.2021. [Epub ahead of print]
    Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia.
    Anthony M Hunter, Hannah Newman, Amy E DeZern, David P Steensma, Sandrine Niyongere, Gail J Roboz, Qianxing Mo, Onyee Chan, Aaron Gerds, David A Sallman, William Dominguez-Viqueira, Christopher Letson, Maria E Balasis, Markus Ball, Traci Kruer, Hailing Zhang, Jeffrey E Lancet, Alan F List, Mikkael A Sekeres, Rami S Komrokji, Eric Padron.
       PURPOSE: CMML is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to GM-CSF and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biologic features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.
    PATIENTS AND METHODS: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase 1/2 clinical study, with a ruxolitinib dose of 20mg twice daily studied in phase 2. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.
    RESULTS: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by MDS/MPN IWG criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials.
    CONCLUSIONS: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-0935
  20. Cancer Discov. 2021 Jul 16.
    Several Types of Mutations Contribute to the Landscape of Clonal Hematopoiesis.
      SNVs/indels and CNAs occur individually and together in clonal hematopoiesis and can affect the same genes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-101
  21. Bone Marrow Transplant. 2021 Jul 10.
    Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT.
    Frédéric Baron, Maud Ngoya, Myriam Labopin, Jan J Cornelissen, Arnold Ganser, Edouard Forcade, Henrik Sengeloev, Gérard Socié, Didier Blaise, Martin Bornhäuser, Thomas Valerius, Hans Christian Reinhardt, Nicolaus Kröger, Annalisa Ruggeri, Arnon Nagler, Mohamad Mohty.
      Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
    DOI:  https://doi.org/10.1038/s41409-021-01387-7
  22. Leukemia. 2021 Jul 09.
    Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.
    L C Stetson, Dheepa Balasubramanian, Susan Pereira Ribeiro, Tammy Stefan, Kalpana Gupta, Xuan Xu, Slim Fourati, Anne Roe, Zachary Jackson, Robert Schauner, Ashish Sharma, Banumathi Tamilselvan, Samuel Li, Marcos de Lima, Tae Hyun Hwang, Robert Balderas, Yogen Saunthararajah, Jaroslaw Maciejewski, Thomas LaFramboise, Jill S Barnholtz-Sloan, Rafick-Pierre Sekaly, David N Wald.
      The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.
    DOI:  https://doi.org/10.1038/s41375-021-01338-7
  23. Mol Cancer Ther. 2021 Jul 12. pii: molcanther.0029.2021. [Epub ahead of print]
    Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia.
    Lu Zhang, Tianyu Cai, Xiaoyu Lin, Xiaoli Huang, Mai H Bui, Joshua P Plotnik, Richard J Bellin, Emily J Faivre, Vinitha M Kuruvilla, Lloyd T Lam, Xin Lu, Zheng Zha, Weiguo Feng, Paul Hessler, Tamar Uziel, Qi Zhang, Antonio Cavazos, Lina Han, Debra C Ferguson, Gaurav Mehta, Sriram S Shanmugavelandy, Terrance J Magoc, Jenny Rowe, Neal C Goodwin, Kathleen A Dorritie, Michael Boyiadzis, Daniel H Albert, Keith F McDaniel, Warren M Kati, Marina Konopleva, Yu Shen.
      Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
    DOI:  https://doi.org/10.1158/1535-7163.MCT-21-0029
  24. Oncotarget. 2021 Jul 06. 12(14): 1377-1387
    Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia.
    Maura Argenziano, Chiara Tortora, Alessandra Di Paola, Elvira Pota, Martina Di Martino, Daniela Di Pinto, Caterina Di Leva, Francesca Rossi.
      Pediatric acute myeloid leukemia (AML) represents 20% of total childhood leukemia diagnoses and is characterized by poor prognosis with a long-term survival rate around the 50%, when patients are properly treated. The standard treatment for pediatric AML currently consists in a combination of cytarabine (Ara-C) and antracycline. Iron plays an important role in cancer development and progression. Targeting iron and its metabolism mediators could be a novel therapeutic strategy in cancer.Deferasirox (DFX) inhibits cancer cell proliferation and its use as an antiblastic drug could be suggested. Eltrombopag (ELT), a thrombopoietin receptor agonist used in immunethrombocytopenia, shows anticancer properties related to its emerging iron chelating properties. We compare the anticancer effect of classically used cytarabine with DFX and ELT effects in a pediatric AML cell line, THP-1, in order to identify innovative and more effective therapeutic strategies. ELT and DFX reduce intracellular iron concentration by inhibiting its uptake and by promoting its release. In particular, even though further investigations are needed to better understand the extact underlying action mechanisms, we demonstrated that ELT improves cytarabine antineoplastic activity in pediatric AML cell line.
    Keywords:  acute monocytic leukemia; cancer; deferasirox; eltrombopag; iron chelation
    DOI:  https://doi.org/10.18632/oncotarget.28000
  25. J Hematol Oncol. 2021 Jul 13. 14(1): 110
    Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML.
    Jorge E Cortes, Tara L Lin, Geoffrey L Uy, Robert J Ryan, Stefan Faderl, Jeffrey E Lancet.
       BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up.
    METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses.
    RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology.
    CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.
    Keywords:  Acute myeloid leukemia; Chemotherapy; Quality-of-life; Relapse; Survival; Toxicity
    DOI:  https://doi.org/10.1186/s13045-021-01119-w
  26. Blood Adv. 2021 Jul 13. 5(13): 2740-2750
    A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.
    Lia Perez, Hugo Fernandez, Mohamed Kharfan-Dabaja, Farhad Khimani, Brian Betts, Asmita Mishra, Ernesto Ayala, Frederick L Locke, Leonel Ochoa-Bayona, Michael Nieder, Joseph Pidala, Alex Achille, John Powers, Eva Sahakian, Ram Thapa, Xuefeng Wang, Claudio Anasetti.
      Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004225
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