bims-tremyl 2024-10-20 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2024–10–20
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Inflammation in myelodysplastic syndrome pathogenesis.
Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia.
Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy.
Therapeutic strategies targeting aberrant RNA splicing in myeloid malignancies.
Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia.
Acute myeloid leukemia: does sex matter?
Exposure toxicity of venetoclax in acute myeloid leukemia patients in the real-life setting: impact of high exposure on delayed neutropenia.
Protocol for monitoring clonal hematopoiesis in transgenic mouse models using multispectral imaging.
Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches.
Targeting the Tumour Antigen 5T4 using CAR-T Cells for the Treatment of Acute Myeloid Leukaemia.
Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment.
HMA/VEN treatment modifications and associated outcomes in IDH-mutant AML.
Pacritinib Response Is Associated With Overall Survival in Myelofibrosis: PERSIST-2 Landmark Analysis of Survival.
Targetable treatment resistance in thyroid cancer with clonal hematopoiesis.
Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia.
Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.
Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.
Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.
Measurable residual FLT3 tyrosine kinase domain mutations before allogeneic transplant for acute myeloid leukemia.
Mutant NPM1 marginally impacts ribosome footprint in acute myeloid leukemia cells.
Are we ready for disease modification in myeloproliferative neoplasms?
Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine.
YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.
Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.
Beyond myeloid neoplasms germline guidelines: Validation of the thresholds criteria in the search of germline predisposition variants.
Navigating 'grey areas' and challenges during evaluation of transplant eligibility in specific myelofibrosis populations: a perspective on behalf of the Chronic Malignancies Working Party of the EBMT.
Impact of TP53 in MDS with isolated del(5q).
Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia.
Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations.
Impact of TP53 abnormalities in MDS-del(5q).
Outcomes After Brexucabtagene Autoleucel Administered as a Standard Therapy for Adults With Relapsed/Refractory B-Cell ALL.
A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.
DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells.
A View of Myeloid Transformation through the Hallmarks of Cancer.
Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Semin Hematol. 2024 Sep 21. pii: S0037-1963(24)00107-0. [Epub ahead of print]

Inflammation in myelodysplastic syndrome pathogenesis.

Juan Jose Rodriguez-Sevilla, Simona Colla.

  Inflammation is a key driver of the progression of preleukemic myeloid conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), to myelodysplastic syndromes (MDS). Inflammation is a critical mediator in the complex interplay of the genetic, epigenetic, and microenvironmental factors contributing to clonal evolution. Under inflammatory conditions, somatic mutations in TET2, DNMT3A, and ASXL1, the most frequently mutated genes in CHIP and CCUS, induce a competitive advantage to hematopoietic stem and progenitor cells, which leads to their clonal expansion in the bone marrow. Chronic inflammation also drives metabolic reprogramming and immune system deregulation, further promoting the expansion of malignant clones. This review underscores the urgent need to fully elucidate the role of inflammation in MDS initiation and highlights the potential of the therapeutical targeting of inflammatory pathways as an early intervention in MDS.

Keywords:  Clonal cytopenia of undetermined significance; Clonal hematopoiesis of indeterminate potential; Hematopoietic stem cells; Inflammation; Myelodysplastic syndromes

DOI:  https://doi.org/10.1053/j.seminhematol.2024.09.005
Blood Adv. 2024 Oct 17. pii: bloodadvances.2024014672. [Epub ahead of print]

Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia.

Romane Joudinaud, Augustin Boudry, Laurène Fenwarth, Sandrine Geffroy, Mikaël Salson, Hervé Dombret, Celine Berthon, Arnaud Pigneux, Delphine Lebon, Pierre Peterlin, Simon Bouzy, Pascale Flandrin-Gresta, Emmanuelle Tavernier, Martin Carre, Sylvie Tondeur, Lamya Haddaoui, Raphaël A Itzykson, Sarah Bertoli, Audrey Bidet, Eric Delabesse, Mathilde Hunault, Christan Récher, Claude Preudhomme, Nicolas Duployez, Pierre-Yves Dumas.

Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as the front-line treatment for FLT3-mutated acute myeloid leukemia (AML), complete remission rates are close to 60-70%, and relapses occur in over 40% of cases. Here we studied the molecular mechanisms underlying refractory/relapsed (R/R) situation in FLT3-mutated AML patients. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3-ITD (n=130) and/or FLT3-TKD (n=26) at diagnosis assessed by standard methods. Patients were treated in front-line with ICT + MIDO (n=54) or ICT alone (n=96) according to the diagnosis date and label of MIDO. The evolution of FLT3 clones and co-mutations was analyzed in paired diagnosis-R/R samples by targeted high-throughput sequencing. Using a dedicated algorithm for FLT3-ITD detection, 189 FLT3-ITD microclones (allelic ratio [AR] < 0.05) and 225 macroclones (AR ≥ 0.05) were detected at both time points. At R/R disease, the rate of FLT3-ITD persistence was lower in patients treated with ICT + MIDO compared with patients not receiving MIDO (68% vs. 87.5%, P=0.011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones (referred to as "clonal interference") was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs. single clones: 57%, P=0.049). Considering both treatment groups, if only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% of them became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones and highlight the importance of using sensitive techniques for FLT3--ITD screening in clinical practice.

DOI: https://doi.org/10.1182/bloodadvances.2024014672
Blood Adv. 2024 Oct 17. pii: bloodadvances.2024013687. [Epub ahead of print]

Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy.

Geoffrey L Uy, Vinod A Pullarkat, Praneeth Baratam, Robert K Stuart, Roland B Walter, Eric S Winer, Qi Wang, Stefan Faderl, Divya Chakravarthy, Diane Menno, Ronald S Cheung, Tara L Lin.

Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX‑351 intravenously on days 1 and 3 plus venetoclax 400 mg orally on days 2-21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary endpoints were the RP2D and safety of CPX‑351 combined with venetoclax. Secondary endpoints included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17/35 (49%) patients, all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1/8 (13%) patients with a mutation in TP53, and CR/CRi was achieved by 15/26 (58%) patients with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04038437.

DOI: https://doi.org/10.1182/bloodadvances.2024013687
Br J Haematol. 2024 Oct 15.

Therapeutic strategies targeting aberrant RNA splicing in myeloid malignancies.

Leora Boussi, Jeetayu Biswas, Omar Abdel-Wahab, Eytan Stein.

  In recent years, large-scale sequencing efforts have identified targetable driver mutations in haematopoietic stem cells. These efforts have led to the development and approval of nine novel agents for relapsed or refractory acute myelogenous leukaemia (R/R AML). However, despite an expansion in targeted therapies, achieving a durable remission in AML and high-risk myelodysplastic syndrome (HR-MDS) remains a significant challenge, and there is an urgent need for new effective treatments. Modulation of aberrant RNA splicing has emerged as a novel therapeutic approach in myeloid diseases. Aberrant splicing drives dysregulated gene expression that promotes tumourigenesis through increased proliferation and metastatic potential, immune evasion, decreased apoptosis, and chemotherapy resistance. Mutations in spliceosomal components have been identified in numerous cancer subtypes, with mutations in RNA binding proteins SF3B1, SRSF2, U2AF1, and ZRSR2 occurring frequently in AML and in up to 60% of patients with MDS, as well as in chronic myelomonocytic leukaemia and in 10% of patients with chronic lymphocytic leukaemia. In this review, we explore therapeutic strategies targeting aberrant splicing and the potential of these approaches to drive clinical responses.

Keywords:  MDS; acute leukaemia; clinical trials

DOI:  https://doi.org/10.1111/bjh.19826
Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01215-4. [Epub ahead of print]43(11): 114864

Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia.

Daniel Sjövall, Sudip Ghosh, Narcis Fernandez-Fuentes, Talia Velasco-Hernandez, Anna Hogmalm, Pablo Menendez, Jenny Hansson, Carolina Guibentif, Pekka Jaako.

  Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an increase in ribosome biogenesis and deregulation of the transcription factor landscape. Finally, we demonstrate that defective ribosome assembly shows antileukemia efficacy in p53-deficient AML. Our study unveils the critical requirement of a high protein synthesis rate for leukemia progression and highlights ribosome assembly as a therapeutic target in AML.

Keywords:  AML; CP: Cancer; MLL; eIF6; leukemia; leukemia stem cell; mRNA translation; protein synthesis; ribosome; scRNA-seq

DOI:  https://doi.org/10.1016/j.celrep.2024.114864
Leukemia. 2024 Oct 14.

Acute myeloid leukemia: does sex matter?

Jesse M Tettero, Jacqueline Cloos, Lars Bullinger.

DOI: https://doi.org/10.1038/s41375-024-02435-z
Haematologica. 2024 Oct 17.

Exposure toxicity of venetoclax in acute myeloid leukemia patients in the real-life setting: impact of high exposure on delayed neutropenia.

Florent Puisset, Emmanuel Raffoux, Lionel Ades, Tony Huynh, Raphaël Itzykson, Didier Bouscary, Loréa Aguinana, Florence Rabian, Marie Sebert, Anne Vekhoff, Eolia Brissot, Mohamad Mohty, Agnes Bonnin, Alexis Genthon, Jeremie Zerbit, Lise Willems, Justine Decrocq, Adrien Contejean, Etienne Lengline, Samia Mourah, Lauriane Goldwirt.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.286062
STAR Protoc. 2024 Oct 17. pii: S2666-1667(24)00527-6. [Epub ahead of print]5(4): 103362

Protocol for monitoring clonal hematopoiesis in transgenic mouse models using multispectral imaging.

Priyanka Khanna, Lauren B Ostermann, Shayaun Khazaei, Ran Zhao, Michael Andreeff, Rasoul Pourebrahim.

  Clonal hematopoiesis involves the clonal expansion of hematopoietic cells, potentially progressing into hematological malignancies. Here, we present a protocol for the development and characterization of two mouse models designed to simulate clonal hematopoiesis and acute myeloid leukemia. We describe steps for model generation, monitoring clonal expansion, harvesting, fixation, and staining of bone marrow and spleen tissues. We specifically focus on the visualization and analysis of p53 mutant clonal expansions, providing a comprehensive protocol for studying these phenomena in mouse models. For complete details on the use and execution of this protocol, please refer to Pourebrahim et al.1.

Keywords:  cancer; cell biology; flow cytometry; microscopy; model organisms

DOI:  https://doi.org/10.1016/j.xpro.2024.103362
Adv Biol Regul. 2024 Oct 09. pii: S2212-4926(24)00043-5. [Epub ahead of print] 101055

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches.

Andrea Pellagatti, Jacqueline Boultwood.

  The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including SF3B1, SRSF2 and U2AF1, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of U2AF1 and SF3B1 mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene IRAK4, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

Keywords:  Acute myeloid leukemia; IRAK1/4 inhibitors; IRAK4; Myelodysplastic syndromes; NF-κB signaling; Splicing factor gene mutations

DOI:  https://doi.org/10.1016/j.jbior.2024.101055
Mol Cancer Ther. 2024 Oct 10.

Targeting the Tumour Antigen 5T4 using CAR-T Cells for the Treatment of Acute Myeloid Leukaemia.

Richard Harrop, Daniel G Blount, Naeem Khan, Mayowa Soyombo, Laura Moyce, Mark T Drayson, Jenny Down, Michelle A Lawson, Deirdre O'Connor, Rachael Nimmo, Yatish Lad, Bernard Souberbielle, Kyriacos Mitrophanous, Anna Ettorre.

Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and eradicate tumours. 5T4 is a tumour-associated antigen expressed on the cell surface of most solid tumours. However, very little is known about its expression in haematological malignancies. Herein, we assess the expression of 5T4 in different types of leukaemias, specifically Acute Myeloid Leukaemia (AML), and normal haematopoietic stem cells (HSCs). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR-T cells against HSCs and AML tumour cell lines. 5T4 expression was seen in about 50% of AML cases, specifically AML with mutated NPM1, AML-MR and NOS. 5T4 CAR-T cells efficiently and specifically killed AML tumour cell lines, including the Leukaemic Stem Cells. Co-culture of 5T4 CAR-T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A murine model for AML demonstrated that CAR-T cells recognise and kill in vivo 5T4-expressing tumour cells. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR-T cells can be considered a powerful personalised therapeutic approach to treat AML.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0052
Blood Cancer Discov. 2024 Oct 18. OF1-OF17

Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment.

Deepak Singhal, Monika M Kutyna, Christopher N Hahn, Mithun Vinod Shah, Devendra K Hiwase.

Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy-induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment. Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0103
Leuk Lymphoma. 2024 Oct 14. 1-9

HMA/VEN treatment modifications and associated outcomes in IDH-mutant AML.

Kuo-Kai Chin, Andriy Derkach, Christopher Famulare, Gaurav K Gupta, P Dayand Borge, Mark B Geyer, Aaron D Goldberg, Tamanna Haque, Jae H Park, Lindsey E Roeker, Martin S Tallman, Maximilian Stahl, Eytan M Stein.

  Hypomethylating agents (HMA) and venetoclax (VEN) are commonly used in patients with IDH-mutated (IDHm) acute myeloid leukemia (AML) ineligible for induction chemotherapy. While prior studies demonstrated high response and survival rates with HMA/VEN in IDHm AML, the impact of treatment modifications in real-world settings is unclear. We retrospectively reviewed 89 IDHm AML patients treated with HMA/VEN from January 2018 to June 2023. CR/CRi rates were 76% in newly diagnosed (ND) and 55% in relapsed/refractory (R/R) patients, and median overall survival was 29.2 months (ND) and 17.1 months (R/R), respectively. Treatment modifications were common. Early VEN reductions were associated with lower response rates but not worse survival. Prolonged cycles were not associated with worse response rates or survival. Significant neutropenia and ED visits or unplanned hospitalizations were considerable before and after CR/CRi, though febrile neutropenia decreased afterward. HMA/VEN is efficacious, with treatment modifications not affecting survival, though long-term toxicities are notable.

Keywords:  Acute myeloid leukemia; hypomethylating agent; intensive chemotherapy; venetoclax

DOI:  https://doi.org/10.1080/10428194.2024.2411436
Eur J Haematol. 2024 Oct 14.

Pacritinib Response Is Associated With Overall Survival in Myelofibrosis: PERSIST-2 Landmark Analysis of Survival.

Helen Ajufo, Jan Philipp Bewersdorf, Claire Harrison, Francesca Palandri, John Mascarenhas, Jeanne Palmer, Aaron Gerds, Jean-Jacques Kiladjian, Sarah Buckley, Andriy Derkach, Karisse Roman-Torres, Raajit K Rampal.

  Spleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST-2 study. Patients on study at the start of the 12-week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non-responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non-responders (HR, 0.00; 95% CI, 0.00-0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781.

Keywords:  myelofibrosis; overall survival; pacritinib; spleen volume; total symptom score

DOI:  https://doi.org/10.1111/ejh.14321
bioRxiv. 2024 Oct 11. pii: 2024.10.10.617685. [Epub ahead of print]

Targetable treatment resistance in thyroid cancer with clonal hematopoiesis.

Vera Tiedje, Pablo Sánchez Vela, Julie L Yang, Brian R Untch, Laura Boucai, Aaron J Stonestrom, Alberto Bueno Costa, Sebastià Franch Expósito, Avi Srivastava, Marina Kerpelev, Jillian Greenberg, Mathew Wereski, Amanda Kulick, Kevin Chen, Tianyue Qin, Soo-Yeon Im, Aishwarya Krishnan, Anthony R Martinez Benitez, Raquel Pluvinet, Merve Sahin, Kamal Menghrajani, Gnana P Krishnamoorthy, Elisa de Stanchina, Ahmet Zehir, Rahul Satija, Jeffrey Knauf, Robert L Bowman, Manel Esteller, Sean Devlin, Michael F Berger, Richard P Koche, James A Fagin, Ross L Levine.

Anaplastic thyroid cancer (ATC) is a clinically aggressive malignancy with a dismal prognosis. Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients with BRAF V600E -mutant ATCs. However, relapses are common and overall survival remains poor. Compared with differentiated thyroid cancer, a hallmark of ATCs is significant infiltration with myeloid cells, particularly macrophages. ATCs are most common in the aging population, which also has an increased incidence of TET2 -mutant clonal hematopoiesis (CH). CH-mutant macrophages have been shown to accelerate CH-associated pathophysiology including atherosclerosis. However, the clinical and mechanistic contribution of CH-mutant clones to solid tumour biology, prognosis and therapeutic response has not been elucidated. Here we show that TET2 -mutant CH is enriched in the tumour microenvironment of patients with solid tumours and associated with adverse prognosis in ATC patients. We find that Tet2 -mutant macrophages selectively infiltrate mouse Braf V600E -mutant ATC and that their overexpression of Tgfβ-family ligands mediates resistance to BRAF/MEK inhibition. Importantly, inhibition of Tgfβ signaling restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH.

DOI: https://doi.org/10.1101/2024.10.10.617685
Curr Treat Options Oncol. 2024 Oct 16.

Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia.

Justin M Watts, Simon J Shaw, Brian A Jonas.

   OPINION STATEMENT: Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

Keywords:  2-hydroxyglutarate; Alpha-ketoglutarate; Isocitrate dehydrogenase; Mutant IDH1

DOI:  https://doi.org/10.1007/s11864-024-01264-7
Cell Death Dis. 2024 Oct 16. 15(10): 750

Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.

Mahesh Tambe, Sarah Unterberger, Mette C Kriegbaum, Ida Vänttinen, Ezgi June Olgac, Markus Vähä-Koskela, Mika Kontro, Krister Wennerberg, Caroline A Heckman.

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.

DOI: https://doi.org/10.1038/s41419-024-07140-4
Leukemia. 2024 Oct 15.

Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.

Chenwei Yang, Yixin Hu, Li Gao, Zhiheng Li, Yongping Zhang, Ran Zhuo, Yayun Du, Hu Liu, Qi Ji, Minyuan Liu, Jian Pan, Jun Lu, Peifang Xiao, Yuanyuan Tian, Sudan He, Jing Ling, Shaoyan Hu.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.

DOI: https://doi.org/10.1038/s41375-024-02437-x
J Clin Oncol. 2024 Oct 17. JCO2400490

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) and the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL)

PURPOSE: The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL.
PATIENTS AND METHODS: EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS).
RESULTS: Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study.
CONCLUSION: Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

DOI: https://doi.org/10.1200/JCO.24.00490
Bone Marrow Transplant. 2024 Oct 18.

Measurable residual FLT3 tyrosine kinase domain mutations before allogeneic transplant for acute myeloid leukemia.

Pranay S Hegde, Georgia Andrew, Gege Gui, Niveditha Ravindra, Devdeep Mukherjee, Zoë C Wong, Jeffery J Auletta, Firas El Chaer, Adam Corner, Steven M Devine, Antonio Martin Jimenez Jimenez, Marcos J G De Lima, Mark R Litzow, Partow Kebriaei, Wael Saber, Stephen R Spellman, Scott L Zeger, Kristin M Page, Laura W Dillon, Christopher S Hourigan.

DOI: https://doi.org/10.1038/s41409-024-02444-7
EJHaem. 2024 Oct;5(5): 1028-1032

Mutant NPM1 marginally impacts ribosome footprint in acute myeloid leukemia cells.

Lorenzo Brunetti, Giulia Pianigiani, Michael C Gundry, Margaret A Goodell, Brunangelo Falini.

   Background: NPM1-mutated acute myeloid leukemia (AML) is the most frequent AML subtype. As wild-type NPM1 is known to orchestrate ribosome biogenesis, it has been hypothesized that altered translation may contribute to leukemogenesis and leukemia maintenance in NPM1-mutated AML. However, this hypothesis has never been investigated. We reasoned that if mutant NPM1 (NPM1c) directly impacts translation in leukemic cells, loss of NPM1c would result in acute changes in the ribosome footprint.
Methods: Here, we performed ribosome footprint profiling (Ribo-seq) and bulk messenger RNA (mRNA) sequencing in two NPM1-mutated cell lines engineered to express endogenous NPM1c fused to the FKBP (F36V) degron tag (degron cells).
Results and discussion: Incubation of degron cells with the small compound dTAG-13 enables highly specific degradation of NPM1c within 4 hours. As expected, RNA-sequencing data showed early loss of homeobox gene expression following NPM1c degradation, confirming the reliability of our model. In contrast, Ribo-seq data showed negligible changes in the ribosome footprint in both cell lines, implying that the presence of NPM1c does not influence ribosome abundance and positioning on mRNA. While it is predictable that NPM1c exerts its leukemogenic activity at multiple levels, ribosome footprint does not seem influenced by the presence of mutant NPM1.

Keywords:  acute leukemia; cell biology; transcription

DOI:  https://doi.org/10.1002/jha2.996
Hemasphere. 2024 Sep;8(9): e70003

Are we ready for disease modification in myeloproliferative neoplasms?

Claire N Harrison.

DOI: https://doi.org/10.1002/hem3.70003
Eur J Haematol. 2024 Oct 13.

Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine.

Helena Bresser, Claudia Schmoor, Olga Grishina, Dietmar Pfeifer, Johanna Thomas, Usama-Ur Rehman, Martina Crysandt, Edgar Jost, Felicitas Thol, Michael Heuser, Katharina S Götze, Richard F Schlenk, Helmut R Salih, Marcus M Schittenhelm, Gerhard Heil, Carsten Schwaenen, Carsten Müller-Tidow, Wolfram Brugger, Andrea Kündgen, Maike de Wit, Aristoteles Giagounidis, Sebastian Scholl, Andreas Neubauer, Jürgen Krauter, Gesine Bug, Annette M May, Ralph Wäsch, Justus Duyster, Konstanze Döhner, Arnold Ganser, Hartmut Döhner, Björn Hackanson, Heiko Becker, Michael Lübbert.

  In a randomized phase II trial (AMLSG 14-09, NCT00867672) of elderly, newly diagnosed AML patients, ATRA combined with decitabine (DEC) significantly improved the overall response rate (ORR) and survival also in patients with adverse-risk genetics, without adding toxicity. We performed a post hoc analysis to determine the predictive impact of TP53 status. Despite a nominally higher ORR, the clinically meaningful survival benefit when adding ATRA to DEC was diminished, but not completely negated, in TP53-mutated patients. Indeed, 2 out of 14 TP53-mutated patients (14%) randomized to a DEC + ATRA-containing regimen lived for > 36 months. Further studies of ATRA combined with hypomethylating agents appear warranted in non-M3 AML patients ineligible for HMA/venetoclax therapy. Trial Registration: ClinicalTrials.gov identifier: NCT00867672.

Keywords:   TP53 ; AML; ATRA; HMA; epigenetics

DOI:  https://doi.org/10.1111/ejh.14304
Cell Death Discov. 2024 Oct 16. 10(1): 439

YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.

Hongna Zuo, Jin Liu, Bin Shen, Yue Sheng, Zhenyu Ju, Hu Wang.

YTHDC1, a reader of N6-methyladenosine (m6A) modifications on RNA, is posited to exert significant influence over RNA metabolism. Despite its recognized importance, the precise function and underlying mechanisms of YTHDC1 in the preservation of normal hematopoietic stem cell (HSCs) homeostasis remain elusive. Here, we investigated the role of YTHDC1 in normal hematopoiesis and HSCs maintenance in vivo. Utilizing conditional Ythdc1 knockout mice and Ythdc1/Mettl3 double knockout mice, we demonstrated that YTHDC1 is required for HSCs maintenance and self-renewal by regulating microRNA maturation. YTHDC1 deficiency resulted in HSCs apoptosis. Furthermore, we uncovered that YTHDC1 interacts with HP1BP3, a nuclear RNA binding protein involved in microRNA maturation. Deletion of YTHDC1 brought about significant alterations in microRNA levels. However, over-expression of mir-125b, mir-99b, and let-7e partially rescued the functional defect of YTHDC1-null HSCs. Taken together, these findings indicated that the nuclear protein YTHDC1-HP1BP3-microRNA maturation axis is essential for the long-term maintenance of HSCs.

DOI: https://doi.org/10.1038/s41420-024-02203-z
Mol Oncol. 2024 Oct 12.

Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.

Tessa S Seale, Li Li, J Kyle Bruner, Melody Chou, Bao Nguyen, Jaesung Seo, Ruiqi Zhu, Mark J Levis, Christine A Pratilas, Donald Small.

  Acute myeloid leukemia (AML) patients with the FMS-related receptor tyrosine kinase 3 internal tandem duplication (FLT3/ITD) mutation have a poorer prognosis, and treatment with FLT3 tyrosine kinase inhibitors (TKIs) has been hindered by resistance mechanisms. One such mechanism is known as adaptive resistance, in which downstream signaling pathways are reactivated after initial inhibition. Past work has shown that FLT3/ITD cells undergo adaptive resistance through the reactivation of extracellular signal-regulated kinase (ERK) signaling within 24 h of sustained FLT3 inhibition. We investigated the mechanism(s) responsible for this ERK reactivation and hypothesized that targeting tyrosine-protein kinase receptor UFO (AXL), another receptor tyrosine kinase that has been implicated in cancer resistance, may overcome the adaptive ERK reactivation. Experiments revealed that AXL is upregulated and activated in FLT3/ITD cell lines mere hours after commencing TKI treatment. AXL inhibition combined with FLT3 inhibition to decrease the ERK signal rebound and to exert greater anti-leukemia effects than with either treatment alone. Finally, we observed that TKI-induced AXL upregulation occurs in patient samples, and combined inhibition of both AXL and FLT3 increased efficacy in our in vivo models. Taken together, these data suggest that AXL plays a role in adaptive resistance in FLT3/ITD AML and that combined AXL and FLT3 inhibition might improve FLT3/ITD AML patient outcomes.

Keywords:  FLT3/ITD AML; RTK signaling; adaptive response; cancer resistance; targeted therapy

DOI:  https://doi.org/10.1002/1878-0261.13749
EJHaem. 2024 Oct;5(5): 1021-1027

Beyond myeloid neoplasms germline guidelines: Validation of the thresholds criteria in the search of germline predisposition variants.

Julia Mestre, Lorea Chaparro, Ana Manzanares, Blanca Xicoy, Lurdes Zamora, Francesc Sole, Oriol Calvete.

   Introduction: Germline predisposition to myeloid neoplasms can be suspected in patients younger than 50 years or when harboring mutations with a variant allele frequency (VAF) higher than 30% for point mutations in specific genes. To investigate the VAF thresholds' accuracy we have explored the prevalence of germline variants below the 30% VAF threshold.
Methods: A total of 40 variants with VAF lower than 30% in bone marrow samples of myeloid neoplasm patients were selected and studied in CD3+ cells.
Results: All the selected variants were not found in CD3+ cells except one variant in the SF3B1 gene. However, the whole series was found somatic. Selected variants were also evaluated with our previously studied series of 52 variants with VAF higher than 30%.
Conclusion: Our study suggests that variants with VAF below 30% are strong somatic candidates but the variants with VAF higher than 30% cannot be considered of germline origin.

Keywords:  germline guidelines; germline predisposition; myelodysplastic syndromes (MDS); variant allele frequency (VAF)

DOI:  https://doi.org/10.1002/jha2.1012
Bone Marrow Transplant. 2024 Oct 14.

Navigating 'grey areas' and challenges during evaluation of transplant eligibility in specific myelofibrosis populations: a perspective on behalf of the Chronic Malignancies Working Party of the EBMT.

Nicola Polverelli, Juan Carlos Hernández-Boluda, Nico Gagelmann, Carmelo Gurnari, Michele Malagola, Fernando Barroso Duarte, Vaneuza A M Funke, Caterina Zerbi, Donal P McLornan.

Significant efforts have been made to effectively select myelofibrosis (MF) patients who can benefit from allogeneic hematopoietic cell transplantation (allo-HCT), the only current cure for MF. The recent EBMT/ELN 2024 recommendations offer valuable guidance for hematologists and transplant physicians. However, several grey areas remain in day-to-day clinical practice regarding the feasibility and optimal preparation for transplantation in patients with this disease. Effective spleen size reduction, often achieved with JAK inhibitors, appears crucial for transplant success. For resistant cases, switching JAK inhibitors, splenectomy, or spleen irradiation may be considered, taking into account patient profiles, treatment availability and center preferences. Managing splanchnic vein thromboses, portal, and pulmonary hypertension is critical as these conditions may affect transplant outcomes. Cytopenias, particularly transfusion-dependent anemia and thrombocytopenia, complicate treatment and impact on outcomes, though new drugs show promise. Comorbidities play a significant role and tools like the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and frailty assessments are useful for evaluating transplant risks while allowing the implementation of corrective measures. Especially in low- and medium-income countries where access to novel therapies may be challenging, allo-HCT still represents an attractive therapeutic option for MF. Future directions include integrating new therapeutics into the transplant algorithm and leveraging artificial intelligence for more informed risk assessment, highlighting the need for tailored approaches to improve allo-HCT outcomes in such a setting.

DOI: https://doi.org/10.1038/s41409-024-02437-6
Blood. 2024 Oct 17. 144(16): 1655-1656

Impact of TP53 in MDS with isolated del(5q).

Lionel Adès.

DOI: https://doi.org/10.1182/blood.2024026010
Sci Rep. 2024 10 12. 14(1): 23882

Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia.

Brunno Gilberto Santos de Macedo, Manuela Albuquerque de Melo, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto, Fabíola Traina.

  Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

Keywords:   Drug resistance; Acute myeloid leukemia; Autophagy; FLT3-ITD inhibitors; Inflammasome

DOI:  https://doi.org/10.1038/s41598-024-74168-z
Haematologica. 2024 Oct 17.

Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations.

Ludovica Marando, Clifford M Csizmar, Mrinal M Patnaik.

Chronic myelomonocytic leukemia (CMML) is an aggressive clonal stem cell disorder categorized amongst myelodysplastic/myeloproliferative (MDS/MPN) overlap neoplasms. While sharing features with both MDS and MPN, CMML has distinct molecular and clinical profiles. The presence of CMML-specific prognostic models, response criteria, and dedicated clinical trials underscores a unique and complex biology. Agerelated changes affecting the bone marrow microenvironment, immune responses, and the intricate balance between epigenetic deregulation and proinflammatory signaling are characteristic of this disease, collectively posing significant scientific and clinical challenges in management. CMML is an ageing-related, clinically heterogeneous neoplasm with limited approved therapeutic options, representing an area of unmet medical need. This review offers a comprehensive analysis of the current understanding of the molecular mechanisms driving CMML evolution and its clinical manifestations within the ever-evolving landscape of precision medicine. In light of the most recent molecular discoveries, we highlight the pitfalls of existing therapies and underscore promising investigational agents. Many of the biological findings discussed are shared across a spectrum of acute and chronic myeloid neoplasms, as well as clonal hematopoiesis, broadening the scope of this review.

DOI: https://doi.org/10.3324/haematol.2024.286061
Blood. 2024 Oct 17. 144(16): 1753

Impact of TP53 abnormalities in MDS-del(5q).

DOI: https://doi.org/10.1182/blood.2024026663
J Clin Oncol. 2024 Oct 17. JCO2400321

Outcomes After Brexucabtagene Autoleucel Administered as a Standard Therapy for Adults With Relapsed/Refractory B-Cell ALL.

ROCCA Consortium

PURPOSE: On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy.
METHODS: We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
RESULTS: At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy.
CONCLUSION: Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

DOI: https://doi.org/10.1200/JCO.24.00321
Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00324-2. [Epub ahead of print]

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.

Taylor S Mills, Bailee Kain, Matt A Burchill, Etienne Danis, Erin D Lucas, Rachel Culp-Hill, Courtney M Cowan, Wolfgang E Schleicher, Sweta B Patel, Brandon T Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A Jirón Tamburini, James R Roede, Angelo D'Alessandro, Katherine Y King, Eric M Pietras.

  Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

Keywords:  autoimmune disease; bone marrow-derived macrophage; hematopoietic stem cell; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.1016/j.stem.2024.09.010
bioRxiv. 2024 Sep 19. pii: 2024.09.15.613155. [Epub ahead of print]

DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells.

Bac Viet Le, Umeshkumar Vekariya, Monika M Toma, Margaret Nieborowska-Skorska, Marie-Christine Caron, Malgorzata Gozdecka, Zayd Haydar, Martin Walsh, Jayashri Ghosh, Elaine Vaughan-Williams, Paulina Podszywalow-Bartnicka, Anna-Mariya Kukuyan, Sylwia Ziolkowska, Emir Hadzijusufovic, Gurushankar Chandramouly, Katarzyna Piwocka, Richard Pomerantz, George S Vassiliou, Brian Jp Huntly, Peter Valent, Alfonso Bellacosa, Jean-Yves Masson, Gaorav P Gupta, Grant A Challen, Tomasz Skorski.

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are usually resistant to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double strand breaks (DSBs) and collapsed replication forks, rendering them dependent on DNA damage response (DDR). DNA polymerase theta (Polθ), a key element in Polθ-mediated DNA end-joining (TMEJ), is essential for survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs was diminished in DNMT3Amut leukemia cells which facilitated loading of Polθ on DNA damage and promoting TMEJ and replication fork restart. Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

DOI: https://doi.org/10.1101/2024.09.15.613155
Blood Cancer Discov. 2024 Oct 18. OF1-OF11

A View of Myeloid Transformation through the Hallmarks of Cancer.

Inés Fernández-Maestre, Sheng F Cai, Ross L Levine.

The development of myeloid malignancies is influenced by a range of cell-intrinsic and cell-extrinsic factors, which can be conceptualized using the hallmarks of cancer. Although many facets of myeloid transformation are similar to those in solid tumors, there are also notable differences. Unlike solid tumors, hematologic malignancies typically exhibit fewer genetic mutations, which have been well characterized. However, understanding the cell-extrinsic factors contributing to myeloid malignancies can be challenging due to the complex interactions in the hematopoietic microenvironment. Researchers need to focus on these intricate factors to prevent the early onset of myeloid transformation and develop appropriate interventions. Significance: Myeloid malignancies are common in the elderly, and acute myeloid leukemia has an adverse prognosis in older patients. Investigating cell-extrinsic factors influencing myeloid malignancies is crucial to developing approaches for preventing or halting disease progression and predicting clinical outcomes in patients with advanced disease. Whereas successful intervention may require targeting various mechanisms, understanding the contribution of each cell-extrinsic factor will help prioritize clinical targets.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0009
Nat Metab. 2024 Oct 14.

Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.

Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.

DOI: https://doi.org/10.1038/s42255-024-01143-3
Nat Metab. 2024 Oct 15.

Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

DOI: https://doi.org/10.1038/s42255-024-01145-1