bims-tremyl 2023-07-09 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2023–07–09
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germ line RUNX1, GATA2, and DDX41 variants.
Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism.
Emerging small molecular inhibitors as targeted therapies for high-risk acute myeloid leukemias.
The ribosomal protein S6 kinase alpha-1 (RPS6KA1) induces resistance to venetoclax/azacitidine in acute myeloid leukemia.
Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.
Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).
Venetoclax with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia.
Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance.
Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.
Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.
Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in acute myeloid leukemia.
Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.
Metformin sensitizes AML cells to venetoclax through endoplasmic reticulum stress-CHOP pathway.
Breaking the loop in AML.
Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1.
Clonal hematopoiesis, aging and Alzheimer's disease.
Impact of Donor Age on Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults with Acute Myeloid Leukemia.
Activation of distinct inflammatory pathways in subgroups of LR-MDS.
Dasatinib with intensive chemotherapy in de novo paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (CA180-372/COG AALL1122): a single-arm, multicentre, phase 2 trial.
PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.
Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.
De novo detection of somatic mutations in high-throughput single-cell profiling data sets.
Author Correction: Clonal haematopoiesis and risk of chronic liver disease.
The role of m6A demethylase FTO in chemotherapy resistance mediating acute myeloid leukemia relapse.
Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability.
A Journey Through JAK Inhibitors for the Treatment of Myeloproliferative Diseases.
Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.
Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms.
Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.
Oncogene-like addiction to aneuploidy in human cancers.
Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.
CSF3R-mutant chronic myelomonocytic leukemia is a distinct clinically subset with abysmal prognosis: a case report and systematic review of the literature.

Blood Adv. 2023 Jul 05. pii: bloodadvances.2023010045. [Epub ahead of print]

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germ line RUNX1, GATA2, and DDX41 variants.

Claire C Homan, Michael W Drazer, Kai Yu, David Michael Lawrence, Jinghua Feng, Luis Alberto Arriola-Martinez, Matthew J Pozsgai, Kelsey E McNeely, Thuong Thi Ha, Parvathy Venugopal, Peer Arts, Sarah King-Smith, Jesse Jc Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B Cantor, Mario Cazzola, Erin S Degelman, Courtney D DiNardo, Nicolas Duployez, Rémi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Natsoulis Georges, Carolyn Owen, Keyur P Patel, Claude Preudhomme, Hana Raslova, Hugh Young Rienhoff, Tim Ripperger, Rachael R Schulte, Kiran Tawana, Elvira Velloso, Yan Benedict, Erika Mijin Kwon Kim, Raman Sood, Amy P Hsu, Steven M Holland, Kerry Phillips, Nicola Poplawski, Milena Babic, Andrew H Wei, Cecily J Forsyth, Helen Mar Fan, Ian Lewis, Julian P Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra K Hiwase, Belinda Phipson, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul P Liu, Lucy A Godley, Anna L Brown.

Individuals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.

DOI: https://doi.org/10.1182/bloodadvances.2023010045
bioRxiv. 2023 Jun 01. pii: 2023.05.31.543132. [Epub ahead of print]

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism.

Bryan Harris, Dinesh K Singh, Monika Verma, Shawn P Fahl, Michele Rhodes, Shanna R Sprinkle, Minshi Wang, Yong Zhang, Jaqueline Perrigoue, Rachel Kessel, Suraj Peri, Joshua West, Orsi Giricz, Jacqueline Boultwood, Andrea Pellagatti, K H Ramesh, Cristina Montagna, Kith Pradhan, Jeffrey W Tyner, Brian K Kennedy, Michael Holinstat, Ulrich Steidl, Stephen Sykes, Amit Verma, David L Wiest.

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells.
Highlights: RPL22 insufficiency is observed in MDS/AML and is associated with reduced survivalRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesisRpl22-deficiency does not impair global protein synthesis by HSCRpl22 controls leukemia cell survival by non-canonical regulation of lipid oxidation eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through effects on ALOX12 expression, a regulator of fatty acid oxidation.

DOI: https://doi.org/10.1101/2023.05.31.543132
Expert Rev Hematol. 2023 Jul 05.

Emerging small molecular inhibitors as targeted therapies for high-risk acute myeloid leukemias.

Kieran D Sahasrabudhe, Mary Albrethsen, Alice S Mims.

   INTRODUCTION: Acute Myeloid Leukemia (AML) is an aggressive disease which has traditionally been treated with intensive chemotherapy. Survival in patients with high risk cytogenetic and molecular subsets has been poor with this approach due to suboptimal responses seen with intensive chemotherapy and due to many patients with higher risk disease being older and unable to tolerate intensive therapies. In recent years, several targeted therapies have been under investigation for patients with high-risk AML subsets.
AREAS COVERED: This review covers four different subsets of high-risk AML including TP53-mutated, KMT2A-rearranged, FLT3-mutated, and secondary AML developing after prior hypomethylating agent exposure. The research discussed in this review focuses on small molecule inhibitors that have been studied in the treatment of these high-risk AML subsets.
EXPERT OPINION: There are several small molecule inhibitors that have demonstrated promise in these high-risk AML subsets. Longer follow up and ongoing investigation is needed to continue to optimize therapy for patients with high-risk AML.

Keywords:  Acute Myeloid Leukemia; FLT3; KMT2A; Small molecule inhibitors; TP53; Targeted therapeutics

DOI:  https://doi.org/10.1080/17474086.2023.2233701
Leukemia. 2023 Jul 06.

The ribosomal protein S6 kinase alpha-1 (RPS6KA1) induces resistance to venetoclax/azacitidine in acute myeloid leukemia.

Katharina Weidenauer, Christina Schmidt, Christian Rohde, Cornelius Pauli, Maximilian F Blank, Daniel Heid, Alexander Waclawiczek, Anika Corbacioglu, Stefanie Göllner, Michelle Lotze, Lisa Vierbaum, Simon Renders, Jeroen Krijgsveld, Simon Raffel, Tim Sauer, Andreas Trumpp, Caroline Pabst, Carsten Müller-Tidow, Maike Janssen.

Venetoclax/azacitidine combination therapy is effective in acute myeloid leukemia (AML) and tolerable for older, multimorbid patients. Despite promising response rates, many patients do not achieve sustained remission or are upfront refractory. Identification of resistance mechanisms and additional therapeutic targets represent unmet clinical needs. By using a genome-wide CRISPR/Cas9 library screen targeting 18,053 protein- coding genes in a human AML cell line, various genes conferring resistance to combined venetoclax/azacitidine treatment were identified. The ribosomal protein S6 kinase A1 (RPS6KA1) was among the most significantly depleted sgRNA-genes in venetoclax/azacitidine- treated AML cells. Addition of the RPS6KA1 inhibitor BI-D1870 to venetoclax/azacitidine decreased proliferation and colony forming potential compared to venetoclax/azacitidine alone. Furthermore, BI-D1870 was able to completely restore the sensitivity of OCI-AML2 cells with acquired resistance to venetoclax/azacitidine. Analysis of cell surface markers revealed that RPS6KA1 inhibition efficiently targeted monocytic blast subclones as a potential source of relapse upon venetoclax/azacitidine treatment. Taken together, our results suggest RPS6KA1 as mediator of resistance towards venetoclax/azacitidine and additional RPS6KA1 inhibition as strategy to prevent or overcome resistance.

DOI: https://doi.org/10.1038/s41375-023-01951-8
Lancet Haematol. 2023 Jul 03. pii: S2352-3026(23)00117-5. [Epub ahead of print]

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

Li Xuan, Yu Wang, Kaibo Yang, Ruoyang Shao, Fen Huang, Zhiping Fan, Peiru Chi, Yajing Xu, Na Xu, Lan Deng, Xudong Li, Xinquan Liang, Xiaodan Luo, Pengcheng Shi, Hui Liu, Zhixiang Wang, Ling Jiang, Ren Lin, Yan Chen, Sanfang Tu, Yu Zhang, Jing Sun, Xiaojun Huang, Qifa Liu.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial.
METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete.
FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths.
INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT.
FUNDING: None.
TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

DOI: https://doi.org/10.1016/S2352-3026(23)00117-5
Bone Marrow Transplant. 2023 Jul 07.

Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).

Eleni Gavriilaki, Ioanna Sakellari, Myriam Labopin, Martin Bornhäuser, Rose-Marie Hamladji, Jochen Casper, Matthias Edinger, Pavel Zák, Ibrahim Yakoub-Agha, Fabio Ciceri, Thomas Schroeder, Tsila Zuckerman, Guido Kobbe, Moshe Yeshurun, Franco Narni, Jürgen Finke, Jose Luiz Diez-Martin, Ana Berceanu, Inken Hilgendorf, Mareike Verbeek, Attilio Olivieri, Bipin Savani, Alexandros Spyridonidis, Arnon Nagler, Mohamad Mohty.

We compared FT14 (fludarabine 150-160 mg/m2, treosulfan 42 g/m2) versus FB4 (fludarabine 150-160 mg/m2, busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.

DOI: https://doi.org/10.1038/s41409-023-02028-x
Res Sq. 2023 Jun 12. pii: rs.3.rs-3015916. [Epub ahead of print]

Venetoclax with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia.

Ian Michael Bouligny, Graeme Murray, Thuy Ho, Michael Doyel, Tilak Patel, Josh Boron, Valerie Tran, Juhi Gor, Yiwei Hang, Yanal Alnimer, Kyle Zacholski, Chad Venn, Nolan A Wages, Steven Grant, Keri R Maher.

Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS , KRAS , and FLT3 -ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.

DOI: https://doi.org/10.21203/rs.3.rs-3015916/v1
Cell Death Discov. 2023 Jul 06. 9(1): 228

Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance.

Ghizlane Choukrani, Nienke Visser, Natasha Ustyanovska Avtenyuk, Mirjam Olthuis, Glenn Marsman, Emanuele Ammatuna, Harm Jan Lourens, Toshiro Niki, Gerwin Huls, Edwin Bremer, Valerie R Wiersma.

Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but was negatively associated with autophagic flux. Importantly, both AraC-sensitive and -resistant AML cell lines, as well as AML patient samples, were sensitive to single-agent treatment with Gal-9. Additionally, Gal-9 potentiated the cytotoxic effect of DNA demethylase inhibitor Azacytidine (Aza), a drug that is clinically used for patients that are not eligible for intensive AraC treatment. Thus, Gal-9 is a potential therapeutic agent for the treatment of AML, including AraC-resistant AML, by inducing caspase-independent cell death.

DOI: https://doi.org/10.1038/s41420-023-01515-w
bioRxiv. 2023 May 30. pii: 2023.05.29.542723. [Epub ahead of print]

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Dharaniya Sakthivel, Alexandra N Brown-Suedel, Francesca Keane, Shixia Huang, Kenneth Mc Sherry, Chloé I Charendoff, Kevin P Dunne, Dexter J Robichaux, BaoChau Le, Crystal S Shin, Alexandre F Carisey, Jonathan M Flanagan, Lisa Bouchier-Hayes.

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm ( NPM1c+ ). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm, and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ AML but not in NPM1wt cells. Strikingly, in NPM1c+ cells, loss of caspase-2 results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells with and without caspase-2. Together, these results show that caspase-2 is essential for proliferation and self-renewal of AML cells that have mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function and may even be a druggable target to treat NPM1c+ AML and prevent relapse.

DOI: https://doi.org/10.1101/2023.05.29.542723
PLoS One. 2023 ;18(7): e0288162

Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.

Sandro Trova, Fei Lin, Santosh Lomada, Matthew Fenton, Bhavini Chauhan, Alexandra Adams, Avani Puri, Alessandro Di Maio, Thomas Wieland, Daniel Sewell, Kirstin Dick, Daniel Wiseman, Deepti P Wilks, Margaret Goodall, Mark T Drayson, Farhat L Khanim, Christopher M Bunce.

A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1β from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1β secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-κB and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1β in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases.

DOI: https://doi.org/10.1371/journal.pone.0288162
Leukemia. 2023 Jul 01.

Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in acute myeloid leukemia.

Jun Liu, Suji Min, Dongchan Kim, Jihyun Park, Eunchae Park, Shanshan Pei, Youngil Koh, Dong-Yeop Shin, Ja Min Byun, Myunggon Ko, Sung-Soo Yoon, Junshik Hong.

Vitamin C has been demonstrated to regulate hematopoietic stem cell frequencies and leukemogenesis by augmenting and restoring Ten-Eleven Translocation-2 (TET2) function, potentially acting as a promising adjunctive therapeutic agent for leukemia. However, glucose transporter 3 (GLUT3) deficiency in acute myeloid leukemia (AML) impedes vitamin C uptake and abolishes the clinical benefit of vitamin C. In this study, we aimed to investigate the therapeutic value of GLUT3 restoration in AML. In vitro GLUT3 restoration was conducted with the transduction of GLUT3-overexpressing lentivirus or the pharmacological salvage with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) treatment to OCI-AML3, a naturally GLUT3-deficient AML cell line. The effects of GLUT3 salvage were further confirmed in patient-derived primary AML cells. Upregulation of GLUT3 expression made AML cells successfully augment TET2 activity and enhanced the vitamin C-induced anti-leukemic effect. Pharmacological GLUT3 salvage has the potential to overcome GLUT3 deficiency in AML and improves the antileukemic effect of vitamin C treatments.

DOI: https://doi.org/10.1038/s41375-023-01954-5
Res Sq. 2023 Jun 16. pii: rs.3.rs-2444524. [Epub ahead of print]

Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.

Jessica Pham, Jane Isquith, Maria Rivera, Haoran Zhang, Qingchem Zhou, Roman Sasik, Adam Mark, Wenxue Ma, Frida Holm, Kathleen Fisch, Dennis Kuo, Catriona Jamieson, Qingfei Jiang.

Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA and retains unedited nuclear dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents a safe and effective therapeutic strategy for eliminating T-ALL LICs.

DOI: https://doi.org/10.21203/rs.3.rs-2444524/v2
Br J Haematol. 2023 Jul 06.

Metformin sensitizes AML cells to venetoclax through endoplasmic reticulum stress-CHOP pathway.

Lei Hua, Nianhui Yang, Yue Li, Kexiu Huang, Xinya Jiang, Fangshu Liu, Zhi Yu, Jie Chen, Jing Lai, Juan Du, Hui Zeng.

  Venetoclax inhibits acute myeloid leukaemia by inhibiting BCL-2 targeting, and a combination regimen with venetoclax has been explored. Although these regimens produce better clinical results, the vast majority of patients still suffer from disease recurrence or primary drug resistance. Metformin has been demonstrated to induce apoptosis in cancer cells. However, whether it can synergize with venetoclax and the underlying mechanisms of metformin-induced apoptosis are not fully understood. In this study, we investigated the effect of metformin and venetoclax on the growth of AML cells in vitro and in vivo. In both Molm13 and THP-1 cell lines, metformin and venetoclax synergistically inhibited the proliferation and induced apoptosis of leukaemia cells. Most importantly, the combination of metformin and venetoclax treatment significantly increased the expression levels of the endoplasmic reticulum (ER) stress-related marker CHOP, for example, in AML cell lines. Knockdown of CHOP markedly attenuated the metformin- and venetoclax-induced cell apoptosis. Moreover, the combination of metformin and venetoclax demonstrated prominent anti-leukaemia effects in xenograft models and bone marrow samples from AML patients. In summary, the combination of metformin and venetoclax showed enhanced anti-leukaemia activity with acceptable safety in AML patients, representing a new combinatorial strategy worth further clinical investigation to treat AML.

Keywords:  CHOP; acute myeloid leukaemia; apoptosis; endoplasmic reticulum stress; metformin

DOI:  https://doi.org/10.1111/bjh.18968
Blood. 2023 Jul 06. 142(1): 6-7

Breaking the loop in AML.

Daniel J Hodson.

DOI: https://doi.org/10.1182/blood.2023020672
Mol Oncol. 2023 Jul 06.

Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1.

Iva Trsova, Andrea Hrustincova, Zdenek Krejcik, David Kundrat, Aleš Holoubek, Karolina Staflova, Lucie Janstova, Sarka Vanikova, Katarina Szikszai, Jiri Klema, Petr Rysavy, Monika Belickova, Monika Kaisrlikova, Jitka Vesela, Jaroslav Cermak, Anna Jonasova, Jiri Dostal, Jan Fric, Jan Musil, Michaela Dostalova Merkerova.

  Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.

Keywords:  Myelodysplastic neoplasms; SF3B1; ZEB1; circular RNA; splicing

DOI:  https://doi.org/10.1002/1878-0261.13486
Nat Med. 2023 Jul 04.

Clonal hematopoiesis, aging and Alzheimer's disease.

Pablo Sánchez Vela, Jennifer J Trowbridge, Ross L Levine.

DOI: https://doi.org/10.1038/s41591-023-02406-4
Transplant Cell Ther. 2023 Jul 03. pii: S2666-6367(23)01380-5. [Epub ahead of print]

Impact of Donor Age on Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults with Acute Myeloid Leukemia.

Muhammad Bilal Abid, Noel Estrada-Merly, Mei-Jie Zhang, Karen Chen, David Allan, Christopher Bredeson, Mitchell Sabloff, Guru Subramanian Guru Murthy, Talha Badar, Shahrukh Hashmi, Mahmoud Aljurf, Mark R Litzow, Partow Kebriaei, Christopher S Hourigan, Wael Saber.

   INTRODUCTION: Allogeneic hematopoietic cell transplant (alloHCT) provides cure for older patients with acute myeloid leukemia (AML); however, disease relapse remains a major concern. Based on recent data suggesting that younger donor age confers the greatest benefit among matched unrelated donors (MUD), we attempted to answer a practical question: which donor type provides the best outcomes when an older patient with AML has a matched sibling donor (MSD, also older) vs the best MUD?
METHODS: This retrospective cohort registry study accessed data from Center for International Blood and Marrow Transplant Research database (CIBMTR) in patients with AML 50 years or older undergoing alloHCT from older MSD (aged≥50) or younger MUD (aged≤35) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host-disease (GVHD) prophylaxis. The primary outcome was relapse risk. Secondary outcomes included non-relapse mortality (NRM), GVHD, disease-free survival (DFS), and overall survival (OS).
RESULTS: Among 4684 eligible patients, 1736 underwent alloHCT with an older MSD whereas 2948 received transplant from a younger MUD. In multivariable analysis, compared to an alloHCT from older MSDs, younger MUDs conferred a decreased relapse risk (HR 0.86; p=.005) and a significantly lower adjusted 5-year cumulative incidence of relapse (35% vs 41%; p=.003), but was associated with an increased risk for chronic GVHD (HR 1.18; 95% CI, 1.08-1.29; p=.0002) and greater NRM only in the earlier period from 2011-2015 (HR 1.24; p=.016). The corresponding NRM rates were significantly lower in the more recent period from 2016-2018 (HR 0.78; p=.017). The adjusted 5-year DFS probability was 44% (95% CI, 42%-46%) with an alloHCT from younger MUDs compared to 41% (95% CI, 38%-43%) with an older MSD (p=.04).
CONCLUSION: In older patients with AML undergoing alloHCT, the use of younger MUDs is associated with a decreased relapse risk and improved DFS compared to older MSDs.

Keywords:  Acute myeloid leukemia; Age; Allogeneic hematopoietic cell transplant; Donor; Donor type; Relapse; Stem cell transplantation

DOI:  https://doi.org/10.1016/j.jtct.2023.06.020
Leukemia. 2023 Jul 07.

Activation of distinct inflammatory pathways in subgroups of LR-MDS.

Marie Schneider, Clara Rolfs, Matthias Trumpp, Susann Winter, Luise Fischer, Mandy Richter, Victoria Menger, Kolja Nenoff, Nora Grieb, Klaus H Metzeler, Anne Sophie Kubasch, Katja Sockel, Christian Thiede, Jincheng Wu, Janghee Woo, Andreas Brüderle, Lorenz C Hofbauer, Jörg Lützner, Andreas Roth, Michael Cross, Uwe Platzbecker.

Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.

DOI: https://doi.org/10.1038/s41375-023-01949-2
Lancet Haematol. 2023 Jul;pii: S2352-3026(23)00088-1. [Epub ahead of print]10(7): e510-e520

Dasatinib with intensive chemotherapy in de novo paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (CA180-372/COG AALL1122): a single-arm, multicentre, phase 2 trial.

Stephen P Hunger, Thai Hoa Tran, Vaskar Saha, Meenakshi Devidas, Maria Grazia Valsecchi, Julie M Gastier-Foster, Giovanni Cazzaniga, Shalini C Reshmi, Michael J Borowitz, Anthony V Moorman, Nyla A Heerema, Andrew J Carroll, Patricia Martin-Regueira, Mignon L Loh, Elizabeth A Raetz, Kirk R Schultz, William B Slayton, Gunnar Cario, Martin Schrappe, Lewis B Silverman, Andrea Biondi.

BACKGROUND: The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia.
METHODS: CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged >1 year to <18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m2 orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed.
FINDINGS: Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred.
INTERPRETATION: Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission.
FUNDING: Bristol Myers Squibb.

DOI: https://doi.org/10.1016/S2352-3026(23)00088-1
Leukemia. 2023 Jul 01.

PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

Shuaibing Hou, Xiaomin Wang, Tengxiao Guo, Yanjie Lan, Shengnan Yuan, Shuang Yang, Fei Zhao, Aizhong Fang, Na Liu, Wanzhu Yang, Yajing Chu, Erlie Jiang, Tao Cheng, Xiaojian Sun, Weiping Yuan.

Acute myeloid leukemia (AML) is a major hematopoietic malignancy characterized by the accumulation of immature and abnormally differentiated myeloid cells in bone marrow. Here with in vivo and in vitro models, we demonstrate that the Plant homeodomain finger gene 6 (PHF6) plays an important role in apoptosis and proliferation in myeloid leukemia. Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML in mice. PHF6 depletion inhibited the NF-κB signaling pathways by disrupting the PHF6-p50 complex and partially inhibiting the nuclear translocation of p50 to suppress the expression of BCL2. Treating PHF6 over-expressed myeloid leukemia cells with NF-κB inhibitor (BAY11-7082) significantly increased their apoptosis and decreased their proliferation. Taken together, in contrast to PHF6 as a tumor suppressor in T-ALL as reported, we found that PHF6 also plays a pro-oncogenic role in myeloid leukemia, and thus potentially to be a therapeutic target for treating myeloid leukemia patients.

DOI: https://doi.org/10.1038/s41375-023-01953-6
Leukemia. 2023 Jul 01.

Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.

Erica F Reinig, Jeremy D Rubinstein, Apoorva T Patil, Amanda L Schussman, Vanessa L Horner, Rashmi Kanagal-Shamanna, Jane E Churpek, Daniel R Matson.

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.

DOI: https://doi.org/10.1038/s41375-023-01955-4
Nat Biotechnol. 2023 Jul 06.

De novo detection of somatic mutations in high-throughput single-cell profiling data sets.

Francesc Muyas, Carolin M Sauer, Jose Espejo Valle-Inclán, Ruoyan Li, Raheleh Rahbari, Thomas J Mitchell, Sahand Hormoz, Isidro Cortés-Ciriano.

Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection of somatic mutations in single-cell transcriptomic and ATAC-seq (assay for transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or single-cell DNA sequencing data. SComatic distinguishes somatic mutations from polymorphisms, RNA-editing events and artefacts using filters and statistical tests parameterized on non-neoplastic samples. Using >2.6 million single cells from 688 single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) data sets spanning cancer and non-neoplastic samples, we show that SComatic detects mutations in single cells accurately, even in differentiated cells from polyclonal tissues that are not amenable to mutation detection using existing methods. Validated against matched genome sequencing and scRNA-seq data, SComatic achieves F1 scores between 0.6 and 0.7 across diverse data sets, in comparison to 0.2-0.4 for the second-best performing method. In summary, SComatic permits de novo mutational signature analysis, and the study of clonal heterogeneity and mutational burdens at single-cell resolution.

DOI: https://doi.org/10.1038/s41587-023-01863-z
Nature. 2023 Jul 03.

Author Correction: Clonal haematopoiesis and risk of chronic liver disease.

NHLBI TOPMed Hematology Working Group

DOI: https://doi.org/10.1038/s41586-023-06375-z
Cell Death Discov. 2023 Jul 05. 9(1): 225

The role of m6A demethylase FTO in chemotherapy resistance mediating acute myeloid leukemia relapse.

Zhi-Wei Zhang, Xiao-Su Zhao, Huidong Guo, Xiao-Jun Huang.

Acute myeloid leukemia (AML) is the most common hematopoietic malignancies, and chemotherapy resistance is one of the main causes of relapse. Because of lower survival rate for patients with relapse, it is pivotal to identify etiological factors responsible for chemo-resistance. In this work, direct MeRIP-seq analysis of sequential samples at stage of complete remission (CR) and relapse identifies that dysregulated N6-methyladenosine (m6A) methylation is involved in this progression, and hypomethylated RNAs are related to cell differentiation. m6A demethylase FTO is overexpressed in relapse samples, which enhances the drug resistance of AML cells in vivo and in vitro. In addition, FTO knockdown cells exhibit stronger capacity of differentiation towards granules and myeloid lineages after cytosine arabinoside (Ara-C) treatment. Mechanistically, FOXO3 is identified as a downstream target of FTO, the hypomethylation of FOXO3 mRNA affects its RNA degradation and further reduces its own expression, which ultimately result in attenuated cell differentiation. Collectively, these results demonstrate that FTO-m6A-FOXO3 is the main regulatory axis to affect the chemotherapy resistance of AML cells and FTO is a potential therapeutic target of chemotherapy resistance in AML.

DOI: https://doi.org/10.1038/s41420-023-01505-y
Nat Cell Biol. 2023 Jul 06.

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability.

Vincent Gaggioli, Calvin S Y Lo, Nazaret Reverón-Gómez, Zuzana Jasencakova, Heura Domenech, Hong Nguyen, Simone Sidoli, Andrey Tvardovskiy, Sidrit Uruci, Johan A Slotman, Yi Chai, João G S C Souto Gonçalves, Eleni Maria Manolika, Ole N Jensen, David Wheeler, Sriram Sridharan, Sanjiban Chakrabarty, Jeroen Demmers, Roland Kanaar, Anja Groth, Nitika Taneja.

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

DOI: https://doi.org/10.1038/s41556-023-01167-z
Curr Hematol Malig Rep. 2023 Jul 03.

A Journey Through JAK Inhibitors for the Treatment of Myeloproliferative Diseases.

Andrea Duminuco, Elena Torre, Giuseppe A Palumbo, Claire Harrison.

   PURPOSE OF REVIEW: Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor. The therapeutic approach aims to treat the symptom burden (headache, itching, debilitation), splenomegaly, slow down the fibrotic proliferation in the bone marrow and reduce the risk of thrombosis/bleeding whilst avoiding leukaemic transformation.
RECENT FINDINGS: In recent years, the advent of JAK inhibitors (JAKi) has significantly broadened treatment options for these patients. In myelofibrosis, symptom control and splenomegaly reduction can improve quality of life with improved overall survival, not impacting progression into acute leukaemia. Several JAKi are available and used worldwide, and combination approaches are now being explored. In this chapter, we review the approved JAKi, highlighting its strengths, exploring potential guidelines in choosing which one to use and reasoning towards future perspectives, where the combinations of therapies seem to promise the best results.

Keywords:  Current treatment and future perspectives; Essential thrombocythemia; JAK inhibitors; Myelofibrosis; Polycythaemia vera

DOI:  https://doi.org/10.1007/s11899-023-00702-x
Haematologica. 2023 Jul 06.

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Tania Jain, Hua-Ling Tsai, Hany Elmariah, Pankit Vachhani, Theodoros Karantanos, Sarah A Wall, Lukasz P Gondek, Asad Bashey, Alla Keyzner, Roni Tamari, Michael R Grunwald, Sameem Abedin, Kalyan Vg Nadiminti, Madiha Iqbal, Aaron T Gerds, Auro Viswabandya, Shannon R McCurdy, Monzr M Al Malki, Ravi Varadhan, Haris Ali, Vikas Gupta, Richard J Jones, Salman Otoukesh.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in 7/120 (6%) of patients. At 3 years, nonrelapse mortality (NRM) was 25% (95%CI 17-34%), relapse 27% (95%CI 18-36%), grade 3-4 acute graft versus host disease (GVHD) 12% (95%CI 6-18%), chronic GVHD requiring systemic immunosuppression 14% (95%CI 7-20%), progression-free survival (PFS) 48% (95%CI 39-59%), and overall survival (OS) 56% (95%CI 47-67%). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, sdHR 3.28, 95%CI 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR 2.61, 95%CI 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR 1.98, 95% 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR 2.01, 95% CI 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

DOI: https://doi.org/10.3324/haematol.2023.283426
Br J Haematol. 2023 Jul 03.

Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms.

Anne S Reiner, Benjamin H Durham, Mariko Yabe, Kseniya Petrova-Drus, Jasmine H Francis, Raajit K Rampal, Mario E Lacouture, Veronica Rotemberg, Omar Abdel-Wahab, Katherine S Panageas, Eli L Diamond.

  Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB-approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse-free survival. Relapse is common following treatment interruption however some patients may be suitable for limited-duration treatment.

Keywords:  MAPK pathway; gene targeting; histiocytosis; myeloproliferative disorder; targeted therapy

DOI:  https://doi.org/10.1111/bjh.18964
Nature. 2023 Jul;619(7968): E19-E23

Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.

Chao Mao, Xiaoguang Liu, Yuelong Yan, Kellen Olszewski, Boyi Gan.

DOI: https://doi.org/10.1038/s41586-023-06270-7
Science. 2023 Jul 06. eadg4521

Oncogene-like addiction to aneuploidy in human cancers.

Vishruth Girish, Asad A Lakhani, Sarah L Thompson, Christine M Scaduto, Leanne M Brown, Ryan A Hagenson, Erin L Sausville, Brianna E Mendelson, Pranav K Kandikuppa, Devon A Lukow, Monet Lou Yuan, Eric C Stevens, Sophia N Lee, Klaske M Schukken, Saron M Akalu, Anand Vasudevan, Charles Zou, Barbora Salovska, Wenxue Li, Joan C Smith, Alison M Taylor, Robert A Martienssen, Yansheng Liu, Ruping Sun, Jason M Sheltzer.

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.

DOI: https://doi.org/10.1126/science.adg4521
Cell Death Dis. 2023 Jul 06. 14(7): 403

Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.

Luisa Ricci, Federico Uchenna Stanley, Tanja Eberhart, Francesco Mainini, David Sumpton, Simone Cardaci.

Succinate dehydrogenase (SDH) is the mitochondrial enzyme converting succinate to fumarate in the tricarboxylic acid (TCA) cycle. SDH acts as a tumor suppressor with germline loss-of-function mutations in its encoding genes predisposing to aggressive familial neuroendocrine and renal cancer syndromes. Lack of SDH activity disrupts the TCA cycle, imposes Warburg-like bioenergetic features, and commits cells to rely on pyruvate carboxylation for anabolic needs. However, the spectrum of metabolic adaptations enabling SDH-deficient tumors to cope with a dysfunctional TCA cycle remains largely unresolved. By using previously characterized Sdhb-deleted kidney mouse cells, here we found that SDH deficiency commits cells to rely on mitochondrial glutamate-pyruvate transaminase (GPT2) activity for proliferation. We showed that GPT2-dependent alanine biosynthesis is crucial to sustain reductive carboxylation of glutamine, thereby circumventing the TCA cycle truncation determined by SDH loss. By driving the reductive TCA cycle anaplerosis, GPT2 activity fuels a metabolic circuit maintaining a favorable intracellular NAD+ pool to enable glycolysis, thus meeting the energetic demands of SDH-deficient cells. As a metabolic syllogism, SDH deficiency confers sensitivity to NAD+ depletion achieved by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway. Beyond identifying an epistatic functional relationship between two metabolic genes in the control of SDH-deficient cell fitness, this study disclosed a metabolic strategy to increase the sensitivity of tumors to interventions limiting NAD availability.

DOI: https://doi.org/10.1038/s41419-023-05927-5
Leuk Lymphoma. 2023 Jul 03. 1-8

CSF3R-mutant chronic myelomonocytic leukemia is a distinct clinically subset with abysmal prognosis: a case report and systematic review of the literature.

Vincenzo Guastafierro, Marta Ubezio, Nicla Manes, Chiara Milanesi, Matteo Della Porta, Arturo Bonometti.

  Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) chacaterized by persistent peripheral blood monocytosis, hypercellular bone marrow and dysplasia at least in one myeloid lineage. CMML shares much of its molecular landscape with other myeloid neoplasms, while differs from others such as chronic neutrophilic leukemia (CNL), given the high frequency of CSF3R mutations in the latter. In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.

Keywords:  granulocytes; molecular genetics; morphology; myeloid leukemias and dysplasias; myeloproliferative disorders; stem and primitive progenitor cells

DOI:  https://doi.org/10.1080/10428194.2023.2227750