bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–11–06
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.
  2. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML.
  3. Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia.
  4. Prognostic impact of unsupervised early assessment of bulk and leukemic stem cell measurable residual disease in acute myeloid leukemia.
  5. TP53-altered higher-risk myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a distinct genetic entity with unique unmet needs.
  6. Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling.
  7. Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates.
  8. Resistance to targeted therapies in acute myeloid leukemia.
  9. Revisiting Co-existing Chromosomal Abnormalities in NPM1-mutated AML in Light of the Revised ELN 2022 classification.
  10. Hypodiploidy has Unfavorable Impact on Survival in Pediatric Acute Myeloid Leukemia:An I-BFM Study Group collaboration.
  11. The methyltransferase domain of DNMT1 is an essential domain in acute myeloid leukemia independent of DNMT3A mutation.
  12. An MDM2 degrader for treatment of acute leukemias.
  13. Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients.
  14. Germline DDX41 mutations define a unique subtype of myeloid neoplasms.
  15. C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.
  16. NPM1 mutations may be associated with adverse outcome in the setting of myeloid neoplasms with complex karyotype.
  17. In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.
  18. A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies.
  19. miR-148a-3p and DDX6 functional link promotes survival of myeloid leukemia cells.
  20. Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia patients enrolled in measurable residual disease-oriented trials.
  21. UTX loss alters therapeutic responses in KMT2A-rearranged acute myeloid leukemia.
  22. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes.
  23. MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia.
  24. Single-cell methods in myeloproliferative neoplasms - old questions, new technologies.
  25. Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndrome.
  26. Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.
  27. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.
  28. Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia.
  29. Dasatinib/Prednisone Induction Followed by Blinatumomab/Dasatinib in Ph+ Acute Lymphoblastic Leukemia.
  30. Heterogeneity of the cancer cell line metabolic landscape.
  31. Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations.
  32. A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia.
  33. Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.
  34. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  35. Anemia in myelofibrosis: current and emerging treatment options.
  36. Uncovering the emergence of HSCs in the human fetal bone marrow by single-cell RNA-seq analysis.
  1. J Clin Oncol. 2022 Oct 31. JCO2200715
    Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.
    Tim Grob, Mathijs A Sanders, Christian M Vonk, Franҫois G Kavelaars, Melissa Rijken, Diana W Hanekamp, Patrycja L Gradowska, Jacqueline Cloos, Yngvar Fløisand, Marinus van Marwijk Kooy, Markus G Manz, Gert J Ossenkoppele, Lidwine W Tick, Violaine Havelange, Bob Löwenberg, Mojca Jongen-Lavrencic, Peter J M Valk.
       PURPOSE: The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry.
    METHODS: In 161 patients with de novo FLT3-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS).
    RESULTS: NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P < .001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry.
    CONCLUSION: NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.
    DOI:  https://doi.org/10.1200/JCO.22.00715
  2. Blood Adv. 2022 Nov 02. pii: bloodadvances.2022008316. [Epub ahead of print]
    Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML.
    Ghayas C Issa, Aram Bidikian, Sangeetha Venugopal, Marina Y Konopleva, Courtney D DiNardo, Tapan M Kadia, Gautam Borthakur, Elias J Jabbour, Naveen Pemmaraju, Musa Yilmaz, Nicholas J Short, Abhishek Maiti, Koji Sasaki, Lucia Masarova, Sherry R Pierce, Koichi Takahashi, Guilin Tang, Sanam Loghavi, Keyur P Patel, Michael Andreeff, Kapil N Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Naval G Daver.
      Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in the relapsed/refractory (R/R) settings is unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (1st salvage: 56% vs 37%, P<0.0001); 2nd salvage: 33% vs 22%, P=0.02; 3rd salvage: 24% vs 14%, P=0.02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0, 5.3 vs 4.1, and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS: 15.8 vs 4.6 months, P=0.05; median OS: 14.7 vs 5.9 months, P=0.02). In conclusion, NPM1 mutational status has minimal impact on prognosis in relapsed or refractory AML, therefore equally requiring novel treatment strategies to improve outcomes in this entity.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008316
  3. Leukemia. 2022 Nov 04.
    Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia.
    Assunta Adamo, Paulynn Chin, Peter Keane, Salam A Assi, Sandeep Potluri, Sophie G Kellaway, Daniel Coleman, Luke Ames, Anetta Ptasinska, H Ruud Delwel, Peter N Cockerill, Constanze Bonifer.
      Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by mutations in genes encoding transcriptional and epigenetic regulators together with signaling genes. It is characterized by a disturbance of differentiation and abnormal proliferation of hematopoietic progenitors. We have previously shown that each AML subtype establishes its own core gene regulatory network (GRN), consisting of transcription factors binding to their target genes and imposing a specific gene expression pattern that is required for AML maintenance. In this study, we integrate gene expression, open chromatin and ChIP data with promoter-capture Hi-C data to define a refined core GRN common to all patients with CEBPA-double mutant (CEBPAN/C) AML. These mutations disrupt the structure of a major regulator of myelopoiesis. We identify the binding sites of mutated C/EBPα proteins in primary cells, we show that C/EBPα, AP-1 factors and RUNX1 colocalize and are required for AML maintenance, and we employ single cell experiments to link important network nodes to the specific differentiation trajectory from leukemic stem to blast cells. Taken together, our study provides an important resource which predicts the specific therapeutic vulnerabilities of this AML subtype in human cells.
    DOI:  https://doi.org/10.1038/s41375-022-01744-5
  4. Clin Cancer Res. 2022 Nov 01. pii: CCR-22-2237. [Epub ahead of print]
    Prognostic impact of unsupervised early assessment of bulk and leukemic stem cell measurable residual disease in acute myeloid leukemia.
    Alban Canali, Inès Vergnolle, Sarah Bertoli, Laetitia Largeaud, Marie-Laure Nicolau, Jean-Baptiste Rieu, Suzanne Tavitian, Francoise Huguet, Muriel Picard, Pierre Bories, Jean-Philippe Vial, Nicolas Lechevalier, Marie-Christine Béné, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Christian Recher, Francois Vergez.
       PURPOSE: Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSCs) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet has published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays.
    EXPERIMENTAL DESIGN: We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 AML patients who received intensive conventional chemotherapy treatment.
    RESULTS: The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (Hazard Ratio, HR:3.82, p<0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR:2.84, p=0.001). Interestingly, one-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-.
    CONCLUSION: In this study, we confirm the prognostic impact of post-induction MFC Bulk MRD in AML patients. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2237
  5. Leuk Lymphoma. 2022 Nov 02. 1-11
    TP53-altered higher-risk myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a distinct genetic entity with unique unmet needs.
    Somedeb Ball, Sanam Loghavi, Amer M Zeidan.
      Pathogenic alterations of TP53 are an independent poor prognostic factor in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clinical course of TP53- altered myeloid neoplasms is dictated by genetic characteristics, such as TP53 allelic state and variant allele frequency (VAF), and not the blast count. Hence, it was recently proposed that MDS (with increased blasts) and AML with TP53 alterations may be best classified as a single molecular disease entity, TP53-mutated higher-risk (HR)-MDS/AML. TP53 mutations drive resistance to intensive chemotherapies and less intensive hypomethylating agents (HMA). Novel combinations incorporating BCL2 inhibitor venetoclax improve response rates for TP53-mutated subgroup, but the survival is not improved. Early clinical studies combining HMA with investigational agents demonstrated activity in TP53-mutated HR-MDS/AML, but updated results with larger samples, longer follow-up, or randomized trials were less impressive to date. Future research should focus on finding novel, potentially disease-modifying therapies to improve outcomes in patients with TP53-mutated HR-MDS/AML.
    Keywords:  AML; ICC 2022; MDS; WHO 2022; myeloid malignancy; p53
    DOI:  https://doi.org/10.1080/10428194.2022.2136969
  6. Leuk Res. 2022 Oct 21. pii: S0145-2126(22)00347-2. [Epub ahead of print]123 106971
    Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling.
    Chezi Ganzel, Zhuoxin Sun, Timour Baslan, Yanming Zhang, Mithat Gönen, Omar I Abdel-Wahab, Janis Racevskis, Francine Garrett-Bakelman, Scott W Lowe, Hugo F Fernandez, Rhett Ketterling, Selina M Luger, Mark Litzow, Hillard M Lazarus, Jacob M Rowe, Martin S Tallman, Ross L Levine, Elisabeth Paietta.
      Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0-120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.
    Keywords:  Acute myeloid leukemia; CD25; Flow cytometry; Genomic profiling; MRD; Measurable residual disease; Minimal residual disease
    DOI:  https://doi.org/10.1016/j.leukres.2022.106971
  7. Blood Adv. 2022 Oct 31. pii: bloodadvances.2022008625. [Epub ahead of print]
    Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates.
    Antoine N Saliba, Scott H Kaufmann, Eytan M Stein, Prapti Arvind Patel, Maria R Baer, Wendy Stock, Michael W Deininger, William Blum, Gary J Schiller, Rebecca L Olin, Mark R Litzow, Tara L Lin, Brian John Ball, Michael Boyiadzis, Elie Traer, Olatoyosi Odenike, Martha L Arellano, Alison R Walker, Vu H Duong, Tibor J Kovacsovics, Robert H Collins, Abigail B Shoben, Nyla A Heerema, Matthew C Foster, Kevin L Peterson, Paula A Schneider, Molly Martycz, Theophilus Gana, Leonard Rosenberg, Sonja Marcus, Ashley O Yocum, Timothy L Chen, Mona Stefanos, Alice S Mims, Uma Borate, Amy Burd, Brian J Druker, Ross L Levine, John C Byrd, James M Foran.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022008625
  8. Clin Exp Metastasis. 2022 Nov 01.
    Resistance to targeted therapies in acute myeloid leukemia.
    Rabea Mecklenbrauck, Michael Heuser.
      The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment.
    Keywords:  FLT3 inhibitors; Gemtuzumab-ozogamicin; IDH inhibitors; Primary resistance; Venetoclax
    DOI:  https://doi.org/10.1007/s10585-022-10189-0
  9. Blood. 2022 Nov 03. pii: blood.2022018582. [Epub ahead of print]
    Revisiting Co-existing Chromosomal Abnormalities in NPM1-mutated AML in Light of the Revised ELN 2022 classification.
    Linus Angenendt, Christoph Röllig, Pau Montesinos, Farhad Ravandi, Gunnar Juliusson, Christian Récher, Raphaël A Itzykson, Zdenek Racil, Andrew H Wei, Christoph Schliemann.
      
    DOI:  https://doi.org/10.1182/blood.2022018582
  10. Blood Adv. 2022 Nov 04. pii: bloodadvances.2022008251. [Epub ahead of print]
    Hypodiploidy has Unfavorable Impact on Survival in Pediatric Acute Myeloid Leukemia:An I-BFM Study Group collaboration.
    Anne Sofie Borg Hammer, Kristian Løvvik Juul-Dam, Julie Damgaard Sandahl, Jonas Abrahamsson, Malgorzata Czogala, Emmanuelle Delabesse, Iren Haltrich, Kirsi Jahnukainen, E Anders Kolb, Gábor T Kovács, Guy Leverger, Franco Locatelli, Riccardo Masetti, Ulrika Noren-Nystrom, Susana Raimondi, Mareike Rasche, Dirk Reinhardt, Tomohiko Taki, Daisuke Tomizawa, Bernward Zeller, Henrik Hasle, Eigil Kjeldsen.
      Hypodiploidy, defined as modal number (MN) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed 2000 to 2015 from fourteen childhood AML groups from the international Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs 45 (n=66), 44 (n=10), and 43 (n=5). The most frequent chromosomes lost were 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52% for the hypodiploid cohort. Children with MN≤44 (n=15) had inferior EFS (21%) and OS (33%) compared to children with MN=45 (n=66, EFS: 37%, OS: 56%). Adjusted Hazard ratios were to 4.9 (p=0.001) and 6.1 (p=0.003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n=18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5, p=0.42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in patients treated with SCT in CR1.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008251
  11. Commun Biol. 2022 Nov 03. 5(1): 1174
    The methyltransferase domain of DNMT1 is an essential domain in acute myeloid leukemia independent of DNMT3A mutation.
    Balpreet Bhogal, Barbara A Weir, Ramona Crescenzo, Ann Marien, Min Chul Kwon, Ulrike Philippar, Glenn S Cowley.
      Aberrant DNA methylation patterns are a prominent feature of cancer. Methylation of DNA is mediated by the DNA methyltransferase (DNMT) protein family, which regulates de novo (DNMT3A and DNMT3B) and maintenance (DNMT1) methylation. Mutations in DNMT3A are observed in approximately 22% of acute myeloid leukemia (AML). We hypothesized that DNMT1 or DNMT3B could function as a synthetic lethal therapeutic strategy for DNMT3A-mutant AML. CRISPR-Cas9 tiling screens were performed to identify functional domains within DNMT1/DNMT3B that exhibited greater dependencies in DNMT3A mutant versus wild-type cell lines. Although increased sensitivity to DNMT1 mutation was observed in some DNMT3A mutant cellular models tested, the subtlety of these results prevents us from basing any conclusions on a synthetic lethal relationship between DNMT1 and DNMT3A. Our data suggests that a therapeutic window for DNMT1 methyltransferase inhibition in DNMT3A-driven AML may exist, but validation in more biologically relevant models is required.
    DOI:  https://doi.org/10.1038/s42003-022-04139-5
  12. Leukemia. 2022 Oct 29.
    An MDM2 degrader for treatment of acute leukemias.
    Bridget K Marcellino, Xiaobao Yang, H Ümit Kaniskan, Claudia Brady, He Chen, Karie Chen, Xing Qiu, Cara Clementelli, Lauren Herschbein, Zhijun Li, Sebastian Elghaity-Beckley, Joann Arandela, Brianna Kelly, Ronald Hoffman, Jing Liu, Yue Xiong, Jian Jin, Alan H Shih.
      In acute myeloid leukemia (AML), p53 tumor suppressor activity can be reduced due to enhanced expression of MDM2 which promotes the degradation of p53. In TP53 wild-type malignancies, therapy with small molecule antagonists of MDM2 results in antileukemic activity. Current treatment strategies, however, have been limited by poor tolerability and incomplete clinical activity. We have developed a proteolysis-targeting chimera (PROTAC) MS3227 that targets MDM2 by recruiting the E3 ligase Von Hippel-Lindau, resulting in proteasome-dependent degradation of MDM2. In WT TP53 leukemia cell lines, MS3227 led to activation of p53 targets p21, PUMA, and MDM2 and resulted in cell-cycle arrest, apoptosis, and decreased viability. The catalytic PROTAC MS3227 led to more potent activation when compared to a stoichiometric inhibitor, in part by dampening the negative feedback mechanism in the p53 - MDM2 circuit. The effectiveness of MS3227 was also observed in primary patient specimens with selectivity towards leukemic blasts. The addition of MS3227 enhanced the activity of other anti-leukemic agents including azacytidine, cytarabine, and venetoclax. In particular, MS3227 treatment was shown to downregulate MCL-1, a known mediator of resistance to venetoclax. A PROTAC-based approach may provide a means of improving MDM2 inhibition to gain greater therapeutic potential in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01735-6
  13. Hemasphere. 2022 Nov;6(11): e792
    Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients.
    Marguerite-Marie Le Pannérer, Jeannine Diesch, Raquel Casquero, Michael Maher, Olga Garcia, Torsten Haferlach, Johannes Zuber, Andrea Kündgen, Katharina S Götze, Marcus Buschbeck.
      Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by dysplasia, ineffective hematopoiesis, and predisposition to secondary acute myeloid leukemias (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond to AZA and eventually all patients relapse. Response-predicting biomarkers and combinatorial drugs targets enhancing therapy response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including 4 genes encoding components of Imitation SWItch chromatin remodeling complex pointing toward a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the expression of a gene panel in bone marrow samples from 36 MDS patients subsequently receiving AZA. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as NSUN3 that correlated with increased overall survival. Taken together, we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely nonoverlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.
    DOI:  https://doi.org/10.1097/HS9.0000000000000792
  14. Blood. 2022 Nov 02. pii: blood.2022018221. [Epub ahead of print]
    Germline DDX41 mutations define a unique subtype of myeloid neoplasms.
    Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Claire Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steven Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro Marshall Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Müller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Satoru Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G Kulasekararaj, Lucy A Godley, Jaroslaw P Maciejewski, Seishi Ogawa.
      Germline DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here, enrolling a total of 346 patients with DDX41 pathogenic/likely pathogenic (P/LP) germline variants and/or somatic mutations from 9,082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients, we performed a comprehensive characterization of DDX41-mutated MNs. P/LP DDX41 germline variants explained ~80% of known germline predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n=4,461) compared to a Japanese general population (n=20,238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs. 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years old but rapidly increased to 49% by 90 years of age. DDX41-mutated MDS patients rapidly progressed to AML, which was, however, confined to those having truncating variants. Co-mutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and -WT cases, where none of the co-mutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multi-hit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System (IPSS-R/M). Our findings establish that DDX41-mutated MDS defines a unique subtype of MNs that is distinct from other MNs.
    DOI:  https://doi.org/10.1182/blood.2022018221
  15. Blood. 2022 Nov 02. pii: blood.2022017046. [Epub ahead of print]
    C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.
    Li-Xue Yang, Cheng-Tao Zhang, Meng-Ying Yang, Xue-Hong Zhang, Hong-Chen Liu, Chen-Hui Luo, Yue Jiang, Zhang-Man Wang, Zhong-Yin Yang, Zhao-Peng Shi, Yi-Ci Yang, Ruo-Qu Wei, Li Zhou, Jun Mi, Ai-Wu Zhou, Zhi-Rong Yao, Li Xia, Jin-Song Yan, Ying Lu.
      Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from an AML patient presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset which is enriched within cutis and existed in BM prior to EMI manifestations was identified and further verified in multiple AML patients. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of EMI patients that expressed high level of C1Q. RNA-sequencing and quantitative proteomics analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAFB, endowed leukemia cells with tissue-infiltration ability which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-gC1QR recognition and subsequent stimulation of TGF-β1. This cell-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as an adverse prognostic marker of AML which orchestrates cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.
    DOI:  https://doi.org/10.1182/blood.2022017046
  16. Leuk Res. 2022 Sep 28. pii: S0145-2126(22)00191-6. [Epub ahead of print]123 106965
    NPM1 mutations may be associated with adverse outcome in the setting of myeloid neoplasms with complex karyotype.
    Maximiliano Ramia de Cap, Leo P Wu, German A Pihan, Damodaran Narayanan, Elizabeth A Morgan, Geraldine S Pinkus, Paola Dal Cin, Stephanie N Hurwitz, Adam Bagg, Sanjay S Patel, Wayne Tam, Madhu M Ouseph, Jeffrey Gagan, Yazan F Madanat, Alexa Siddon, Philipp W Raess, Heesun J Rogers, Carlos E Bueso-Ramos, Rashmi Kanagal-Shamanna, Jason H Kurzer, Daniel A Arber, Robert P Hasserjian, Olga K Weinberg.
      
    Keywords:  AML; Cancer; Genetics; Leukemia; Myeloid Sarcoma; NPM1; Oncology; Pathology
    DOI:  https://doi.org/10.1016/j.leukres.2022.106965
  17. Leukemia. 2022 Nov 04.
    In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.
    Anna-Katharina Wirth, Lucas Wange, Sebastian Vosberg, Kai-Oliver Henrich, Christian Rausch, Erbey Özdemir, Christina M Zeller, Daniel Richter, Tobias Feuchtinger, Markus Kaller, Heiko Hermeking, Philipp A Greif, Daniela Senft, Vindi Jurinovic, Ehsan Bahrami, Ashok Kumar Jayavelu, Frank Westermann, Matthias Mann, Wolfgang Enard, Tobias Herold, Irmela Jeremias.
      Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.
    DOI:  https://doi.org/10.1038/s41375-022-01726-7
  18. Blood. 2022 Nov 02. pii: blood.2022018193. [Epub ahead of print]
    A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies.
    Byung-Chul Lee, Yifan Zhou, Erica Bresciani, Neval Ozkaya, Alina Dulau Florea, Blake Carrington, Tae-Hoon Shin, Valentina Baena, Zulfeqhar A Syed, So Gun Hong, Tao Zhen, Katherine R Calvo, Paul P Liu, Cynthia E Dunbar.
      Germline loss-of-function heterozygous mutations in the RUNX1 gene cause Familial Platelet Disorder with associated Myeloid Malignancies (FPDMM), characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant HSPCs in vivo long-term. We generated a rhesus macaque (RM) FPDMM competitive repopulation model using CRISPR/Cas9 NHEJ editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous hematopoietic stem and progenitor cells (HSPCs) and tracked mutation allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared to AAVS1-edited cells. Platelet counts remained below the normal range long-term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous-mutated HSPCs long-term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse MDS/AML predisposition and thrombopoietic defects.
    DOI:  https://doi.org/10.1182/blood.2022018193
  19. Blood Adv. 2022 Nov 02. pii: bloodadvances.2022008123. [Epub ahead of print]
    miR-148a-3p and DDX6 functional link promotes survival of myeloid leukemia cells.
    Maryam Ghashghaei, Cong Truc Le, Haya Shaalan, Leo Escano, Marty Yue, Aaremish Arsalan, Arefeh Rouhi, Tuan Anh Nguyen, Ly Phuong Vu.
      Regulation of gene expression at the RNA level is an important regulatory mechanism in cancers. However, post-transcriptional molecular pathways underlying tumorigenesis remain largely unexplored. In this study, we uncovered a functional axis consisting of microRNA (miR)-148a-3p, RNA helicase DDX6, and its downstream target TXNIP in Acute Myeloid Leukemia (AML). Using a DROSHA-knockout cell system to evaluate miR-mediated gene expression control, we comprehensively profiled putative transcripts regulated by miR-148a-3p and identified DDX6 as a direct target of miR-148a-3p in AML cells. DDX6 depletion induced cell cycle arrest, apoptosis, and differentiation while delaying leukemia development in vivo. Genome-wide assessment of DDX6 binding transcripts and gene expression profiling of DDX6-depleted cells revealed TXNIP, a tumor suppressor, as the functional downstream target of DDX6. Overall, our study identified DDX6 as a post-transcriptional regulator that is required for AML survival. We proposed the regulatory link between miR-148a-3p and DDX6 as a potential therapeutic target in leukemia.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008123
  20. Haematologica. 2022 Nov 03.
    Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia patients enrolled in measurable residual disease-oriented trials.
    Celia González-Gil, Mireia Morgades, Thaysa Lopes, Francisco Fuster-Tormo, Jesús García-Chica, Ran Zhao, Pau Montesinos, Anna Torrent, Marina Diaz-Beya, Rosa Coll, Lourdes Hermosín, Santiago Mercadal, José González-Campos, Lurdes Zamora, Teresa Artola, Ferran Vall-Llovera, Mar Tormo, Cristina Gil-Cortés, Pere Barba, Andrés Novo, Jordi Ribera, Teresa Bernal, Paula López De Ugarriza, María-Paz Queipo, Pilar Martínez-Sánchez, Alicia Giménez, Teresa González-Martínez, Antonia Cladera, José Cervera, Rosa Fernández-Martín, María Ángeles Ardaiz, María Jesús Vidal, Ángela Baena, Nuria López-Bigas, Anna Bigas, Jaroslaw Maciejewski, Alberto Orfao, Josep Maria Ribera, Eulalia Genescà.
      Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the nonleukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined WOG signature and MRD on day +35 allowed risk-stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) (95% confidence interval [CI]) of 52% (37-67 %) and 17% (1-33%), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.
    DOI:  https://doi.org/10.3324/haematol.2022.281196
  21. Leukemia. 2022 Oct 29.
    UTX loss alters therapeutic responses in KMT2A-rearranged acute myeloid leukemia.
    Xinyue Zhou, Pengcheng Zhang, Sajesan Aryal, Lixia Zhang, Rui Lu.
      
    DOI:  https://doi.org/10.1038/s41375-022-01741-8
  22. Am J Hematol. 2022 Oct 30.
    A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes.
    Amer M Zeidan, Uma Borate, Daniel A Pollyea, Andrew M Brunner, Fernando Roncolato, Jacqueline S Garcia, Robin Filshie, Olatoyosi Odenike, Anne Marie Watson, Ravitharan Krishnadasan, Ashish Bajel, Kiran Naqvi, Jiuhong Zha, Wei-Han Cheng, Ying Zhou, David Hoffman, Jason G Harb, Jalaja Potluri, Guillermo Garcia-Manero.
      Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on days 1-7 every cycle at 75 mg/m2/day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR+mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26771
  23. Nat Commun. 2022 Oct 31. 13(1): 6524
    MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia.
    Aristeidis G Telonis, Qin Yang, Hsuan-Ting Huang, Maria E Figueroa.
      DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-022-34211-x
  24. Blood. 2022 Nov 02. pii: blood.2021014668. [Epub ahead of print]
    Single-cell methods in myeloproliferative neoplasms - old questions, new technologies.
    Jennifer M O'Sullivan, Adam J Mead, Bethan Psaila.
      Myeloproliferative neoplasms (MPN) are a group of clonal, stem cell derived hematopoietic malignancies driven by aberrant JAK/STAT signalling. Although they are genetically simple diseases, MPNs are phenotypically heterogeneous, reflecting underlying intra-tumoral heterogeneity driven by the interplay of genetic and non-genetic factors. As their evolution is determined by factors that enable certain cellular subsets to outcompete others, techniques that resolve cellular heterogeneity at the single-cell level are ideally placed to provide new insights into MPN biology. With these insights comes the potential to uncover new approaches to predict the clinical course and treat these cancers, ultimately improving outcomes for patients. MPNs present a particularly tractable model of cancer evolution, as most patients present in an early disease phase and only a small proportion progress to aggressive disease. Therefore, it is not surprising that many of the groundbreaking technological advances in single-cell omics have been pioneered by their application in MPNs. In this review article, we explore how single-cell approaches have provided transformative insights into MPN disease biology, that are broadly applicable across human cancers, and discuss how these studies might be swiftly translated into clinical pathways and may eventually underpin precision medicine.
    DOI:  https://doi.org/10.1182/blood.2021014668
  25. Blood Cancer J. 2022 Nov 04. 12(11): 148
    Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndrome.
    Rami S Komrokji, Avani M Singh, Najla Al Ali, Onyee Chan, Eric Padron, Kendra Sweet, Andrew Kuykendall, Jeffrey E Lancet, David A Sallman.
      
    DOI:  https://doi.org/10.1038/s41408-022-00744-z
  26. Leuk Res. 2022 Oct 22. pii: S0145-2126(22)00346-0. [Epub ahead of print]123 106970
    Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.
    Rose Parisi, Emily A Cowen, Joseph R Stoll, Haoling Zhu, Stephen Dusza, Melissa P Pulitzer, Eytan M Stein, Alina Markova.
      Two novel inhibitors of isocitrate dehydrogenase (IDHi), ivosidenib and enasidenib, significantly improve survival for AML patients with an IDH1 or IDH2 mutation, respectively; however, rash has been reported as a toxicity of IDHi. The objective of our study is to determine the incidence, grade, clinical, and histopathologic features of dermatologic adverse events (DAEs) secondary to IDHi. This study is a retrospective analysis of 169 patients who were treated with either ivosidenib or enasidenib as single agent or in combination with induction chemotherapy at Memorial Sloan Kettering Cancer Center from January 1, 2013 to April 1, 2021. DAEs thought to be possibly, probably, or definitely related to IDHi occurred in 55 of 169 patients [0.32, 95 % CI: 0.25 - 0.40]. Of a total 81 DAEs observed, the most common DAE types were inflammatory dermatoses (27 %); cutaneous vascular manifestations (8%); cutaneous infections (7%); and pruritus (2%). Notably, 50% of infections and 15.5% of rashes were high grade. Knowledge of these findings is critical to optimize the treatment and quality of life of patients with AML on IDHi.
    Keywords:  Acute myeloid leukemia; Adverse events; Cutaneous differentiation syndrome; Dermatology; Oncology; Targeted therapy
    DOI:  https://doi.org/10.1016/j.leukres.2022.106970
  27. Nat Chem Biol. 2022 Nov 03.
    Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.
    Alexander Hanzl, Ryan Casement, Hana Imrichova, Scott J Hughes, Eleonora Barone, Andrea Testa, Sophie Bauer, Jane Wright, Matthias Brand, Alessio Ciulli, Georg E Winter.
      Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.
    DOI:  https://doi.org/10.1038/s41589-022-01177-2
  28. Leukemia. 2022 Oct 29.
    Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia.
    Jayastu Senapati, Elias Jabbour, Hagop Kantarjian, Nicholas J Short.
      The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has been a model for cancer therapy development. Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase (AP) and blast phase (BP), both of which have a relatively poor prognosis. The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. Significant insights have been gained into the mechanisms of disease transformation including the role of additional cytogenetic abnormalities, somatic mutations, and other genomic alterations present at diagnosis or evolving on therapy. This knowledge is helping to optimize TKI therapy, improve prognostication and inform the development of novel combination regimens in these patients. While patients with de novo CML-AP have outcomes almost similar to CML in chronic phase (CP), those transformed from previously treated CML-CP should receive second- or third- generation TKIs and be strongly considered for allogeneic stem cell transplantation (allo-SCT). Similarly, patients with transformed CML-BP have particularly dismal outcomes with a median survival usually less than one year. Combination regimens with a potent TKI such as ponatinib followed by allo-SCT can achieve long-term survival in some transformed BP patients. Regimens including venetoclax in myeloid BP or inotuzumab ozogamicin or blinatumomab in lymphoid BP might lead to deeper and longer responses, facilitating potentially curative allo-SCT for patients with CML-BP once CP is achieved. Newer agents and novel combination therapies are further expanding the therapeutic arsenal in advanced phase CML.
    DOI:  https://doi.org/10.1038/s41375-022-01736-5
  29. Blood Adv. 2022 Nov 02. pii: bloodadvances.2022008216. [Epub ahead of print]
    Dasatinib/Prednisone Induction Followed by Blinatumomab/Dasatinib in Ph+ Acute Lymphoblastic Leukemia.
    Anjali S Advani, Anna Moseley, Kristen M O'Dwyer, Brent L Wood, Jae H Park, Matthew J Wieduwilt, Deepa Jeyakumar, George Yaghmour, Ehab Atallah, Aaron T Gerds, Susan M O'Brien, Jane L Liesveld, Megan Othus, Mark R Litzow, Richard M Stone, Elad Sharon, Harry P Erba.
      Novel treatment strategies are needed for the treatment of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib sensitive fusions/ mutations) were eligible and could be newly diagnosed or relapsed/ refractory. Induction therapy consisted of dasatinib/ prednisone. Patients not achieving response by Day 56 proceeded to blinatumomab re-induction therapy. Patients achieving response with induction or re-induction therapy proceeded to blinatumomab/ dasatinib post-remission therapy for 3 cycles followed by dasatinib/ prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at Days 28, 56, 84, and at additional time points based on response parameters. Measurable residual disease (MRD) was assessed centrally by 8 color flow cytometry at Day 28. Twenty-four eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range 65-87). This combination was safe and feasible. With a median of 2.7 years of follow up, 3-year overall survival and disease-free survival were 87% (95% CI 64%-96%) and 77% (95% CI 54%-90%), respectively. Although longer follow up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial is registered at www.clinicaltrials.gov as NCT02143414.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008216
  30. Mol Syst Biol. 2022 11;18(11): e11006
    Heterogeneity of the cancer cell line metabolic landscape.
    David Shorthouse, Jenna Bradley, Susan E Critchlow, Claus Bendtsen, Benjamin A Hall.
      The unravelling of the complexity of cellular metabolism is in its infancy. Cancer-associated genetic alterations may result in changes to cellular metabolism that aid in understanding phenotypic changes, reveal detectable metabolic signatures, or elucidate vulnerabilities to particular drugs. To understand cancer-associated metabolic transformation, we performed untargeted metabolite analysis of 173 different cancer cell lines from 11 different tissues under constant conditions for 1,099 different species using mass spectrometry (MS). We correlate known cancer-associated mutations and gene expression programs with metabolic signatures, generating novel associations of known metabolic pathways with known cancer drivers. We show that metabolic activity correlates with drug sensitivity and use metabolic activity to predict drug response and synergy. Finally, we study the metabolic heterogeneity of cancer mutations across tissues, and find that genes exhibit a range of context specific, and more general metabolic control.
    Keywords:  cancer; heterogeneity; metabolomics; mutation
    DOI:  https://doi.org/10.15252/msb.202211006
  31. Hematology. 2022 Dec;27(1): 1184-1190
    Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations.
    Yueyue Sun, Fenghong Zhang, Li Huo, Wenzhi Cai, Qinrong Wang, Lijun Wen, Lingzhi Yan, Hongjie Shen, Xiaoyu Xu, Suning Chen.
       OBJECTIVES: Little is known about the clinical impact of germline/somatic mutations of PTPN11 in acute leukemia. The aim of this study was to investigate the clinical characteristics and prognostic impact of PTPN11 mutations in patients with acute myeloid leukemia (AML).
    METHODS: Seventy-four patients with PTPN11 mutation-positive AML treated at our institution were enrolled in this study. The prevalence of PTPN11 mutations was examined using targeted next-generation sequencing technology, and patients with AML and PTPN11 mutations were screened. Clinical characteristics, prognostic impact, and association between PTPN11 mutations and other mutations were analyzed retrospectively.
    RESULTS: PTPN11 mutations co-occurred more commonly with DNMT3A, NPM1, and FLT3 internal tandem duplication mutations. Compared with PTPN11 wild-type (WT) patients, PTPN11 mutation-positive AML patients presented with higher white blood cell (WBC) and platelet (PLT) counts. In 74 PTPN11 positive AML patients, PTPN11 mutations had an adverse effect on overall survival (OS) (62.5%) and a negative prognostic effect on event-free survival (EFS) (50%). Allo-hematopoietic stem cell transplantation (HSCT) abrogated the negative effect of mutations in PTPN11; the OS and EFS of AML patients with PTPN11 mutations who received transplantation were longer than those of AML patients with PTPN11 mutations who did not undergo allo-HSCT (P = 0.001, EFS; P < 0.001, OS). Discussion: Newly diagnosed PTPN11 mutation-positive AML patients with high WBC and PLT counts or presenting no remission after first induction chemotherapy suffer from high mortality rates.
    CONCLUSION: Given the lack of targeted therapies for PTPN11 mutations, timely HSCT is necessary for patients.
    Keywords:  PTPN11 mutations; acute myeloid leukemia; prognosis factor; secondary mutation
    DOI:  https://doi.org/10.1080/16078454.2022.2140274
  32. Blood Cancer Discov. 2022 Nov 02. pii: BCD-22-0098. [Epub ahead of print]
    A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia.
    Olga Lancho, Amartya Singh, Victoria da Silva-Diz, Maya Aleksandrova, Jesminara Khatun, Luca Tottone, Patricia Renck Nunes, Shirley Luo, Caifeng Zhao, Haiyan Zheng, Eric Chiles, Zhenyu Zuo, Pedro P Rocha, Xiaoyang Su, Hossein Khiabanian, Daniel Herranz.
      T-cell Acute Lymphoblastic Leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identified a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which the histone deacetylase SIRT1 is overexpressed downstream of a NOTCH1-bound enhancer. SIRT1 loss impaired leukemia generation, while SIRT1 overexpression accelerated leukemia and conferred resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, pharmacological or genetic inhibition of SIRT1 resulted in significant antileukemic effects. Global acetyl-proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene expression profiling revealed metabolic changes together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. Overall, our results uncovered novel therapeutic targets in T-ALL and revealed a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0098
  33. Blood. 2022 10 31. pii: blood.2022017079. [Epub ahead of print]
    Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.
    Patrizio Panelli, Elisabetta De Santis, Mattia Colucci, Francesco Tamiro, Francesca Sansico, Mattia Miroballo, Emanuele Murgo, Costanzo Padovano, Sam Gusscott, Michele Ciavarella, Elizabeth A Chavez, Fabrizio Bianchi, Giovanni Rossi, Angelo M Carella, Christian Steidl, Andrew P Weng, Vincenzo Giambra.
      T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy, characterized by cell subsets, enriched with leukemia-initiating cells (LIC). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of -Catenin in T-ALL, we performed co-Immunoprecipitation (Co-IP) followed by liquid-chromatography mass spectrometry. Here, we report that a non-canonical functional interaction of β-Catenin with the Forkhead-Box-O3 (FOXO3) transcription factor positively regulates LIC related genes including the Cyclin-dependent-kinase-4 (CDK4), which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-Catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. Additionally, gene expression data at the single-cell level of leukemic cells of primary patients at the diagnosis and minimal residual disease (MRD) up to 30 days from the standard treatments reveal that the expression of β-Catenin and FOXO3 dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). These findings highlight key functional roles for β-Catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL.
    DOI:  https://doi.org/10.1182/blood.2022017079
  34. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  35. Crit Rev Oncol Hematol. 2022 Nov 01. pii: S1040-8428(22)00286-4. [Epub ahead of print] 103862
    Anemia in myelofibrosis: current and emerging treatment options.
    Francesco Passamonti, Claire N Harrison, Ruben A Mesa, Jean-Jacques Kiladjian, Alessandro M Vannucchi, Srdan Verstovsek.
      Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival. The only curative treatment for MF is allogenic stem cell transplantation; however, few patients are eligible. Disease management strategies for MF-related anemia have limited effectiveness, and Janus kinase (JAK) inhibitors may induce or worsen related anemia. Thus, there is a significant unmet need for the treatment of patients with MF-related anemia. This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach.
    Keywords:  Anemia; Myelofibrosis
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103862
  36. Cell Stem Cell. 2022 Nov 03. pii: S1934-5909(22)00423-4. [Epub ahead of print]29(11): 1562-1579.e7
    Uncovering the emergence of HSCs in the human fetal bone marrow by single-cell RNA-seq analysis.
    Zhaofeng Zheng, Han He, Xinyu Thomas Tang, Han Zhang, Fanglin Gou, Hua Yang, Jiaxuan Cao, Shujuan Shi, Zining Yang, Guohuan Sun, Xiaowei Xie, Yang Zeng, Aiqing Wen, Yu Lan, Jiaxi Zhou, Bing Liu, Bo O Zhou, Tao Cheng, Hui Cheng.
      During fetal development, human hematopoietic stem cells (HSCs) colonize the bone marrow (BM), where they self-renew and sustain hematopoiesis throughout life; however, the precise timepoint at which HSCs seed the BM is unclear. We used single-cell RNA-sequencing to map the transcriptomic landscape of human fetal BM and spleen hematopoietic stem/progenitor cells (HSPCs) and their microenvironment from 10 to 14 post-conception weeks (PCWs). We further demonstrated that functional HSCs capable of reconstituting long-term multi-lineage hematopoiesis in adult NOG mice do not emerge in the BM until 12 PCWs. In contrast, functional HSCs were not detected in the spleen by 14 PCWs. By comparing the niche-HSPC interactions between BM and spleen, we identified ligand-receptor pairs likely to be involved in fetal HSC migration and maintenance. Our work paves the way for research into the mechanisms underlying HSC colonization in human fetal BM and provides invaluable resources for future studies on HSC development.
    Keywords:  fetal bone marrow; fetal spleen; hematopoietic stem cell; microenvironment; single cell RNA-seq
    DOI:  https://doi.org/10.1016/j.stem.2022.10.005
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