bims-tremyl 2023-04-09 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023–04–09
38 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia.
Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
Multi-center phase I trial of Ivosidenib as Maintenance Treatment following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia.
The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.
Somatic exonic deletions in RUNX1 constitutes a novel recurrent genomic abnormality in acute myeloid leukemia.
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option.
Noncatalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia.
Human hematopoietic stem cells expand beyond cytokines.
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia.
Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.
Real-world Experience With CPX-351 in High-risk Acute Myeloid Leukemia.
In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts.
TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia.
Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.
Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation.
SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process.
Epigenomic machinery regulating pediatric AML: clonal expansion mechanisms, therapies, and future perspectives.
Response and resistance to cladribine in patients with advanced systemic mastocytosis: a registry-based analysis.
Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3Kδ Downregulation.
Childhood Cancer Treatment and Clonal Hematopoiesis.
Raising the bar for lower-risk myelodysplastic syndromes.
DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells.
IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition.
Alemtuzumab in relapsed immune severe aplastic anemia: Long-term results of a phase II study.
Factors predicting survival following alloSCT in patients with therapy-related AML and MDS: a multicenter study.
Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.
Pivotal role of cytosolic phospholipase PLA2G4A in the pathogenesis of FLT3-ITD-mutated acute myeloid leukemia.
Real-world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption.
Silencing with SAFB: a new role for HOXA9 in AML.
Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival.
Human CD34+ hematopoietic stem cell hierarchy: how far are we with its delineation at the most primitive level?
What role for somatic mutations in systemic inflammatory and autoimmune diseases associated with myelodysplastic neoplasms and chronic myelomonocytic leukemias?
TSTEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models.
IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia.
Patient-reported outcomes from the phase 3 ADMIRAL trial in patients with FLT3-mutated relapsed/refractory AML.
The KMT2A recombinome of acute leukemias in 2023.
The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia.
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.

Cancer Discov. 2023 Apr 03. pii: CD-22-0411. [Epub ahead of print]

C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia.

Marie Sabatier, Rudy Birsen, Laura Lauture, Sarah Mouche, Paolo Angelino, Jonas Dehairs, Lea Goupille, Ismael Boussaid, Mael Heiblig, Emeline Boet, Ambrine Sahal, Estelle Saland, Juliana C Santos, Marc Armengol, Miranda Fernandez-Serrano, Thomas Farge, Guillaume Cognet, Federico Simonetta, Corentin Pignon, Antoine Graffeuil, Celine Mazzotti, Herve Avet-Loiseau, Oceane Delos, Justine Bertrand-Michel, Amelie Chedru, Vilma Dembitz, Paolo Gallipoli, Natasha S Anstee, Sun Loo, Andrew H Wei, Martin Carroll, Armelle Goubard, Remy Castellano, Yves Collette, Francois Vergez, Veronique Mansat-De Mas, Sarah Bertoli, Suzanne Tavitian, Muriel Picard, Christian Recher, Nathalie Bourges-Abella, Fanny Granat, Olivier Kosmider, Pierre Sujobert, Benoit Colsch, Carine Joffre, Lucille Stuani, Johannes V Swinnen, Herve Guillou, Gael Roue, Nawad Hakim, Anne S Dejean, Petros Tsantoulis, Clement Larrue, Didier Bouscary, Jerome Tamburini, Jean-Emmanuel Sarry.

While transcription factor C/AAT-enhancer binding protein a (C/EBPa) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPa and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPa regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPa inactivation decreased mono-unsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPa function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0411
Haematologica. 2023 Apr 06.

Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.

Cristiana O'Brien, Tianyi Ling, Jacob M Berman, Rachel Culp-Hill, Julie A Reisz, Vincent Rondeau, Soheil Jahangiri, Jonathan St-Germain, Vinitha Macwan, Audrey Astori, Andy Zeng, Jun Young Hong, Meng Li, Min Yang, Sadhan Jana, Fabia Gamboni, Emily Tsao, Weiyi Liu, John E Dick, Hening Lin, Ari Melnick, Anastasia Tikhonova, Andrea Arruda, Mark D Minden, Brian Raught, Angelo D'Alessandro, Courtney L Jones.

Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease initiating leukemia stem cells (LSCs). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSCs. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSCs. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSCs but is not essential for normal human hematopoietic stem and progenitor cell (HSPC) function. To elucidate the molecular mechanisms by which SIRT3 is essential in LSCs we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support oxidative phosphorylation and ATP production in human LSCs. Further, we discovered two approaches to further sensitize LSCs to SIRT3 inhibition. First, we found that LSCs tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSCs to YC8-02 and potentiates LSC cell death. Second, SIRT3 inhibition sensitizes LSCs to BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.

DOI: https://doi.org/10.3324/haematol.2022.281894
Clin Cancer Res. 2023 Apr 04. pii: CCR-23-0182. [Epub ahead of print]

Multi-center phase I trial of Ivosidenib as Maintenance Treatment following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia.

Amir T Fathi, Haesook T Kim, Robert J Soiffer, Mark J Levis, Shuli Li, Annette S Kim, Zachariah DeFilipp, Areej El-Jawahri, Steve L McAfee, Andrew M Brunner, Philip C Amrein, Alice S Mims, Laura W Knight, Devon Kelley, Aj S Bottoms, Lindsey H Perry, Jonathan L Wahl, Jennifer Brock, Elayne Breton, Dylan M Marchione, Vincent T Ho, Yi-Bin Chen.

PURPOSE: IDH1 (isocitrate dehydrogenase 1) mutations occur in 5-10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML.
PATIENTS AND METHODS: We conducted a multi-center, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to twelve 28-day cycles. The first dose level was 500mg daily, with level reduction to 250mg daily, if needed, in a 3x3 de-escalation design. Ten additional patients would then receive the maximum tolerated (MTD) or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib.
RESULTS: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and two-year CI of all cGVHD was 63%. Two-year CI of relapse and non-relapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and two-year overall survival (OS) was 88%.
CONCLUSIONS: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase 1 study.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-0182
Biochem Pharmacol. 2023 Apr 04. pii: S0006-2952(23)00130-2. [Epub ahead of print] 115539

The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.

Qian Li, Mengyuan Wang, Lingbo Liu.

  Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.

Keywords:  Acute myeloid leukemia; Bone marrow niche; Drug resistance; Exosomes; Leukemic stem cells; Stemness maintenance

DOI:  https://doi.org/10.1016/j.bcp.2023.115539
Clin Cancer Res. 2023 Apr 06. pii: CCR-23-0122. [Epub ahead of print]

Somatic exonic deletions in RUNX1 constitutes a novel recurrent genomic abnormality in acute myeloid leukemia.

Anna Eriksson, Marie Engvall, Lucy Mathot, Albin Österroos, Martin Rippin, Lucia Cavelier, Claes Ladenvall, Panagiotis Baliakas.

PURPOSE: In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML.
EXPERIMENTAL DESIGN: Sixty well-characterized AML patients were analyzed with Multiplex Ligation-dependent Probe Amplification (MLPA, n=60), micro-array (n=11) and/or whole genome sequencing (WGS, n=8).
RESULTS: In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs 38.8 months respectively, p=0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were re-assigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate and high-risk group (18.9 vs 9.6 months, p=0.09).
CONCLUSIONS: Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk-stratification and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-0122
Blood. 2023 Apr 05. pii: blood.2022016896. [Epub ahead of print]

Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option.

Monika Dolinska, Huan Cai, Alma Mansson, Jingyi Shen, Pingnan Xiao, Thibault Bouderlique, Xidan Li, Elory Leonard, Marcus Chang, Yuchen Gao, Juan Pablo Medina Giménez, Makoto Kondo, Lakshmi Sandhow, Anne-Sofie Johansson, Stefan Deneberg, Stina Söderlund, Martin Jädersten, Johanna S Ungerstedt, Magnus Tobiasson, Arne Östman, Satu Mustjoki, Leif Stenke, Katarina Le Blanc, Eva S Hellstrom-Lindberg, Sören Lehmann, Marja Ekblom, Ulla Olsson-Strömberg, Mikael Sigvardsson, Hong Qian.

Although tyrosine kinase inhibitors are effective for treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be due to bone marrow (BM) niche protection. However, little is known about the underlying mechanisms. We here molecularly and functionally characterized BM niches in CML patients at diagnosis and revealed the altered niche composition and function in the CML patients. Long-term culture initiating cell (LTC-IC) assay showed that the mesenchymal stem cells from CML patients displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in CML patient BM cellular niches. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

DOI: https://doi.org/10.1182/blood.2022016896
Genes Dev. 2023 Apr 06.

Noncatalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia.

Yulia Gonskikh, Julian Stoute, Hui Shen, Krista Budinich, Bianca Pingul, Kollin Schultz, Heidi Elashal, Ronen Marmorstein, Junwei Shi, Kathy Fange Liu.

  Several rRNA-modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18S rRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a noncatalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mislocalizes DIMT1 to the nucleoplasm, in contrast to the primarily nucleolar localization of wild-type DIMT1. Mechanistically, rRNA binding is required for DIMT1 to undergo liquid-liquid phase separation, which explains the distinct nucleoplasm localization of the rRNA binding-deficient DIMT1. Re-expression of wild-type or a catalytically inactive mutant E85A, but not the rRNA binding-deficient DIMT1, supports AML cell proliferation. This study provides a new strategy to target DIMT1-regulated AML proliferation via targeting this essential noncatalytic region.

Keywords:  RNA; cell proliferation; methyltransferase; phase separation

DOI:  https://doi.org/10.1101/gad.350298.122
Cell Stem Cell. 2023 Apr 06. pii: S1934-5909(23)00082-6. [Epub ahead of print]30(4): 343-344

Human hematopoietic stem cells expand beyond cytokines.

Alanna Van Huizen, Shannon McKinney-Freeman.

The paucity of hematopoietic stem cells (HSCs) presents a challenge for both transplantation and the study of HSCs.1 Sakurai et al.2 now present a cytokine-free culture system for robust ex vivo expansion of functional human HSCs that may lead to exciting clinical outcomes.

DOI: https://doi.org/10.1016/j.stem.2023.03.011
Nat Commun. 2023 Apr 05. 14(1): 1882

Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia.

Hanlin Wang, Guanghao Luo, Xiaobei Hu, Gaoya Xu, Tao Wang, Minmin Liu, Xiaohui Qiu, Jianan Li, Jingfeng Fu, Bo Feng, Yutong Tu, Weijuan Kan, Chang Wang, Ran Xu, Yubo Zhou, Jianmin Yang, Jia Li.

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.

DOI: https://doi.org/10.1038/s41467-023-37381-4
Br J Haematol. 2023 Apr 02.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Stéphanie Dulucq, Françoise Rigal-Huguet, Franck E Nicolini, Pascale Cony-Makhoul, Martine Escoffre-Barbe, Martine Gardembas, Laurence Legros, Philippe Rousselot, Jixing Liu, Delphine Rea, Véronique De Mas, Sandrine Hayette, Sophie Raynaud, Caroline Lacoste-Roussillon, Fanny Robbesyn, Emilie Klein, Stéphane Morisset, François-Xavier Mahon, Gabriel Etienne.

  Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Keywords:  CML; TKI discontinuation; nilotinib; second attempt

DOI:  https://doi.org/10.1111/bjh.18796
Crit Rev Oncol Hematol. 2023 Apr 05. pii: S1040-8428(23)00072-0. [Epub ahead of print] 103984

Real-world Experience With CPX-351 in High-risk Acute Myeloid Leukemia.

Roberto M Lemoli, Pau Montesinos, Akriti Jain.

  CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with myelodysplasia-related changes in adults in 2017 (US; updated to patients aged ≥1 year in 2021) and 2018 (EU/UK) based on improved survival and remission and comparable safety versus 7+3 chemotherapy in a randomized trial in older adults. Real-world studies have since evaluated CPX-351 in routine practice across several countries and addressed important data gaps (e.g., use in younger adults, measurable residual disease negativity, outcomes by mutation). This review discusses real-world studies of CPX-351 as AML treatment, with the aim of helping prescribers make informed treatment decisions.

Keywords:  AML; CPX-351; chemotherapy; cytarabine; daunorubicin; measurable residual disease; real-world

DOI:  https://doi.org/10.1016/j.critrevonc.2023.103984
Leukemia. 2023 Apr 06.

In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts.

Gabriele Greve, Geoffroy Andrieux, Pascal Schlosser, Nadja Blagitko-Dorfs, Usama-Ur Rehman, Tobias Ma, Dietmar Pfeifer, Gerhard Heil, Andreas Neubauer, Jürgen Krauter, Michael Heuser, Helmut R Salih, Konstanze Döhner, Hartmut Döhner, Björn Hackanson, Melanie Boerries, Michael Lübbert.

Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1-5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.

DOI: https://doi.org/10.1038/s41375-023-01876-2
Open Med (Wars). 2023 ;18(1): 20220602

TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia.

Wei Zhang, Bei Liu, Shiwen Wu, Li Zhao.

  Acute myeloid leukemia (AML) is classified into favorable-risk, intermediate-risk, and poor-risk subtypes. This study aimed to compare the serum proteomic signatures of the three AML subtypes and identify prognostic biomarkers for AML. Serum samples from patients with favorable-risk (n = 14), intermediate-risk (n = 19), and poor-risk AMLs (n = 18) were used for the analysis of tandem mass tag (TMT) labeling-based quantitative proteomics. Comparative analysis was performed to identify differentially expressed proteins (DEPs) between groups. Prognostic proteins were screened using binary logistics regression analysis. TMT-MS/MS proteomics analysis identified 138 DEPs. Fumarate hydratase (FH), isocitrate dehydrogenase 2 (IDH2), and enolase 1 (ENO1) were significantly upregulated in poor-risk patients compared with favorable-risk patients. ELISA assay confirmed that patients with poor-risk AMLs had higher levels of IDH2, ENO1, and FH compared with intermediate-risk AML patients. Logistics analysis identified that proteins 3-hydroxyacyl-CoA dehydrogenase type-2 (HADH, odds ratio (OR) = 1.035, p = 0.010), glutamine synthetase (GLUL, OR = 1.022, p = 0.039), and lactotransferrin (LTF, OR = 1.1224, p = 0.016) were associated with poor prognosis, and proteins ENO1 (OR = 1.154, p = 0.053), FH (OR = 1.043, p = 0.059), and IDH2 (OR = 3.350, p = 0.055) were associated with AML prognosis. This study showed that AML patients had elevated levels of FH, IDH2, ENO1, LTF, and GLUL proteins and might be at high risk of poor prognosis.

Keywords:  TMT labeling-based quantitative proteomics; favorable-risk acute myeloid leukemia; isocitrate dehydrogenase 2; prognostic biomarker; proteomic profiling

DOI:  https://doi.org/10.1515/med-2022-0602
Cancer Sci. 2023 Apr 07.

Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.

Yoshihiro Hayashi, Hironori Harada.

  Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are a group of clonal hematopoietic stem cell (HSC) diseases. The incidence increases with global population aging. Genome sequencing uncovered mutational profiles in patients with myeloid malignancies and healthy elderly individuals. However, the molecular and cellular basis of disease development remains unclear. Accumulating evidence shows mitochondrial involvement in the pathogenesis of myeloid malignancies, aging-related HSC phenotypes, and clonal hematopoiesis. Mitochondria are dynamic organelles that continuously undergo fission and fusion processes to maintain their function, integrity, and activity. Mitochondria could be a hub of various biological processes that underlie cellular and systemic homeostasis. Thus, mitochondrial dysfunction could directly lead to the disruption of cellular homeostasis and the development of various disorders, including cancer. Notably, emerging data have revealed that mitochondria dynamics also primarily affect not only mitochondrial function and activity but also cellular homeostasis, the aging process, and tumorigenesis. Here, by focusing on mitochondrial dynamics, we highlight the current understanding of mitochondrial roles as a pathobiological mediator of myeloid malignancies and aging-related clonal hematopoiesis.

Keywords:  acute myeloid leukemia; aging; clonal hematopoiesis; mitochondrial dynamics; myelodysplastic syndromes

DOI:  https://doi.org/10.1111/cas.15810
Nat Commun. 2023 Apr 05. 14(1): 1881

Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation.

Nicolas Papadopoulos, Audrey Nédélec, Allison Derenne, Teodor Asvadur Şulea, Christian Pecquet, Ilyas Chachoua, Gaëlle Vertenoeil, Thomas Tilmant, Andrei-Jose Petrescu, Gabriel Mazzucchelli, Bogdan I Iorga, Didier Vertommen, Stefan N Constantinescu.

Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation. Here, we identify the basis of the acquired specificity of CALR mutants for TpoR and define the mechanisms by which complex formation triggers TpoR dimerization and activation. Our work reveals that CALR mutant C-terminus unmasks CALR N-terminal domain, rendering it more accessible to bind immature N-glycans on TpoR. We further find that the basic mutant C-terminus is partially α-helical and define how its α-helical segment concomitantly binds acidic patches of TpoR extracellular domain and induces dimerization of both CALR mutant and TpoR. Finally, we propose a model of the tetrameric TpoR-CALR mutant complex and identify potentially targetable sites.

DOI: https://doi.org/10.1038/s41467-023-37277-3
Front Oncol. 2023 ;13 1116438

SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process.

Moqin Jiang, Meng Chen, Qian Liu, Zhiling Jin, Xiangdong Yang, Weifeng Zhang.

  Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future.

Keywords:  MDS-RS; SF3B1 gene mutation; hyperinflammatory; iron metabolism; myelodysplastic syndromes (MDS); spliceosome; spliceosome inhibitors; splicing factor mutations

DOI:  https://doi.org/10.3389/fonc.2023.1116438
Semin Cancer Biol. 2023 Mar 30. pii: S1044-579X(23)00050-0. [Epub ahead of print]

Epigenomic machinery regulating pediatric AML: clonal expansion mechanisms, therapies, and future perspectives.

Ugo Chianese, Chiara Papulino, Wout Megchelenbrink, Francesco Paolo Tambaro, Fortunato Ciardiello, Rosaria Benedetti, Lucia Altucci.

  Acute myeloid leukemia (AML) is a heterogeneous disease with a genetic, epigenetic, and transcriptional etiology mainly presenting somatic and germline abnormalities. AML incidence rises with age but can also occur during childhood. Pediatric AML (pAML) accounts for 15-20% of all pediatric leukemias and differs considerably from adult AML. Next-generation sequencing technologies have enabled the research community to "paint" the genomic and epigenomic landscape in order to identify pathology-associated mutations and other prognostic biomarkers in pAML. Although current treatments have improved the prognosis for pAML, chemoresistance, recurrence, and refractory disease remain major challenges. In particular, pAML relapse is commonly caused by leukemia stem cells that resist therapy. Marked patient-to-patient heterogeneity is likely the primary reason why the same treatment is successful for some patients but, at best, only partially effective for others. Accumulating evidence indicates that patient-specific clonal composition impinges significantly on cellular processes, such as gene regulation and metabolism. Although our understanding of metabolism in pAML is still in its infancy, greater insights into these processes and their (epigenetic) modulation may pave the way toward novel treatment options. In this review, we summarize current knowledge on the function of genetic and epigenetic (mis)regulation in pAML, including metabolic features observed in the disease. Specifically, we describe how (epi)genetic machinery can affect chromatin status during hematopoiesis, leading to an altered metabolic profile, and focus on the potential value of targeting epigenetic abnormalities in precision and combination therapy for pAML. We also discuss the possibility of using alternative epidrug-based therapeutic approaches that are already in clinical practice, either alone as adjuvant treatments and/or in combination with other drugs.

Keywords:  epigenetic drugs; epigenetics; metabolism; pAML

DOI:  https://doi.org/10.1016/j.semcancer.2023.03.009
Ann Hematol. 2023 Apr 04.

Response and resistance to cladribine in patients with advanced systemic mastocytosis: a registry-based analysis.

Johannes Lübke, Nicole Naumann, Georgia Metzgeroth, Sebastian Kreil, Timo Brand, Hans-Peter Horny, Karl Sotlar, Nicholas C P Cross, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Andreas Reiter, Juliana Schwaab.

  We sought to evaluate the efficacy of the purine analogue cladribine in 79 patients with advanced systemic mastocytosis (AdvSM) using data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. The overall response rate according to modified Valent criteria (46 evaluable patients) for first- (1L) and second-line (2L) cladribine treatment was 41% (12/29) and 35% (6/17, P = 0.690), respectively, and the median overall survival (OS, all patients evaluable) was 1.9 years (n = 48) and 1.2 years (n = 31; P = 0.311). Univariate and multivariable analyses of baseline and on-treatment parameters identified diagnosis of mast cell leukemia (hazard ratio [HR] 3.5, 95% confidence interval [CI, 1.3-9.1], P = 0.012), eosinophilia ≥ 1.5 × 109/L (HR 2.9 [CI 1.4-6.2], P = 0.006) and < 3 cycles of cladribine (HR 0.4 [CI 0.2-0.8], P = 0.008) as independent adverse prognostic parameters for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1) on OS. In consequence, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) was predictive for OS. Modified Valent criteria were superior to a single factor-based response assessment (HR 2.9 [CI 1.3-6.6], P = 0.026). In conclusion, cladribine is effective in 1L and 2L treatment of AdvSM. Mast cell leukemia, eosinophilia, application of < 3 cycles and a lack of response are adverse prognostic markers.

Keywords:  Advanced systemic mastocytosis; Chemotherapy; Cladribine; Purine analogue

DOI:  https://doi.org/10.1007/s00277-023-05180-y
Mol Pharm. 2023 Apr 06.

Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3Kδ Downregulation.

Na An, Yuming Pan, Linlin Yang, Qiongli Zhang, Sisi Deng, Qiaoxia Zhang, Xin Du.

  We previously constructed a nanobody-based anti-CD38 chimeric antigen receptor T (CD38-CAR-T) cell efficiently against multiple myeloma. As CD38 is also expressed on most tumor cells of acute myeloid leukemia (AML), we wondered about its efficacy in treating AML. In this study, we demonstrated that our CD38-CAR-T cells effectively lysed CD38+ AML cell lines, including NB4, U937, HL-60, THP-1 with an E:T (effector/target cells) ratio of 1:8, and primary AML cells from patients with a low E:T ratio of 1:16. Moreover, recent studies showed that inhibition of PI3Kδ could enhance CAR-T-cell efficacy. We constructed PI3Kδ-downregulated CD38-CAR-T cells with a CD38-CAR lentiviral vector containing short hairpin RNA (shRNA) sequences against PI3Kδ. CD38-CAR-T cells with PI3Kδ downregulation maintained their antileukemia function against both AML cell lines and primary AML cells while reducing the release of IL-2, IFN-γ, and TNF when co-culturing with AML cell lines. Both CD38-CAR-T and PI3Kδ-downregulated CD38-CAR-T-cell therapy significantly improved the survival of AML mice, whereas the latter had an even better effect on survival. In summary, our study demonstrated that CD38-CAR-T cells had promising activity against AML, and PI3Kδ downregulation in CD38-CAR-T cells could reduce some cytokines release without impairing their antileukemia function.

Keywords:  CD38; PI3Kδ; acute myeloid leukemia; chimeric antigen receptor; cytokine release syndrome

DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00913
Cancer Discov. 2023 Apr 03. 13(4): 811-813

Childhood Cancer Treatment and Clonal Hematopoiesis.

Grace Collord, Sam Behjati.

SUMMARY: Hagiwara and colleagues investigated the effects of childhood cancer treatment on the clonal composition of blood. Their findings provide strong evidence that treatment promotes clonal outgrowths (clonal hematopoiesis) in childhood cancer survivors. See related article by Hagiwara et al., p. 844 (4).

DOI: https://doi.org/10.1158/2159-8290.CD-23-0090
Leuk Lymphoma. 2023 Apr 08. 1-10

Raising the bar for lower-risk myelodysplastic syndromes.

Sangeetha Venugopal, Mikkael A Sekeres.

  Myelodysplastic syndromes (MDS) are broadly categorized as lower- and higher-risk with lower-risk dominated by cytopenias and higher-risk plagued by the risk of transformation to acute myeloid leukemia (AML). The management of MDS utilize a risk-adapted approach aimed at ameliorating cytopenias in lower-risk MDS (LR-MDS) and preventing AML transformation in higher-risk MDS. Hematopoietic stem cell transplantation is a potentially curative intent therapy in higher-risk MDS; however, it is not routinely recommended in LR-MDS in view of unfavorable risk/benefit ratio. Therefore, the goal of treatment in LR-MDS is aimed at improving the transfusion burden and health related quality of life. Currently, erythropoiesis stimulating agents (recombinant erythropoietin), erythroid maturation agents (luspatercept), disease modifying agents (lenalidomide) and hypomethylating agents are the agents of choice in the treatment of LR-MDS. This review will discuss the current treatment standards, meaningful clinical outcomes, and emerging therapies in LR-MDS.

Keywords:  LR-MDS; MDS; TWiTR; imetelstat; lenalidomide; luspatercept

DOI:  https://doi.org/10.1080/10428194.2023.2197536
Nat Cell Biol. 2023 Apr 06.

DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells.

Raghav Ramabadran, Jarey H Wang, Jaime M Reyes, Anna G Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M Cullen, Siddhartha Tyagi, Danielle Rux, Jean J Kim, Steven M Kornblau, Michael Kyba, Fabio Stossi, Rachel E Rau, Koichi Takahashi, Thomas F Westbrook, Margaret A Goodell.

Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment of the core spliceosome protein SF3B1 to RNA polymerase and mRNA. Importantly, the DNA methylation function of DNMT3A is not required and loss of DNMT3A leads to impaired splicing during stem cell turnover. Finally, we identify the spliceosome as a potential therapeutic target in DNMT3A-mutated leukaemias. Together, our results reveal a modality through which DNMT3A and the spliceosome govern exit from the stem state towards differentiation.

DOI: https://doi.org/10.1038/s41556-023-01109-9
Blood. 2023 Apr 06. pii: blood.2022017948. [Epub ahead of print]

IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition.

Lucien Courtois, Aurelie Cabannes-Hamy, Rathana Kim, Marine Delecourt, Antoine Pinton, Guillaume Charbonnier, Mélanie Féroul, Charlotte Smith, Giulia Tueur, Cecile Pivert, Estelle Balducci, Mathieu Simonin, Laure Hélène Angel, Salvatore Spicuglia, Nicolas Boissel, Guillaume P Andrieu, Vahid Asnafi, Philippe Rousselot, Ludovic Lhermitte.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

DOI: https://doi.org/10.1182/blood.2022017948
Am J Hematol. 2023 Apr 06.

Alemtuzumab in relapsed immune severe aplastic anemia: Long-term results of a phase II study.

Nidhi Aggarwal, Ash Lee Manley, Ruba Shalhoub, Jibran Durrani, Olga Rios, Jennifer Lotter, Bhavisha A Patel, Colin O Wu, Neal S Young, Emma M Groarke.

Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.

DOI: https://doi.org/10.1002/ajh.26924
Bone Marrow Transplant. 2023 Apr 03.

Factors predicting survival following alloSCT in patients with therapy-related AML and MDS: a multicenter study.

Anmol Baranwal, Rakchha Chhetri, David Yeung, Matthew Clark, Syed Shah, Mark R Litzow, William J Hogan, Abhishek Mangaonkar, Hassan B Alkhateeb, Deepak Singhal, Alia Cibich, Peter Bardy, Chung H Kok, Devendra K Hiwase, Mithun Vinod Shah.

Therapy-related myeloid neoplasms (t-MN) are aggressive myeloid neoplasms. Factors predicting post-allogeneic stem cell transplant (alloSCT) survival are not well-known. We studied the prognostic utility of factors at: t-MN diagnosis, pre-alloSCT, and post-alloSCT. Primary endpoints were 3-year overall survival (OS), relapse incidence (RI), and non-relapse mortality (NRM). Post-alloSCT OS did not differ between t-MDS and t-AML (20.1 vs. 19.6 months, P = 1), though t-MDS had a significantly higher 3-year RI compared to t-AML (45.1% vs. 26.9%, P = 0.03). In t-MDS, the presence of monosomy 5 (HR 3.63, P = 0.006) or monosomy 17 (HR 11.81, P = 0.01) pre-alloSCT were associated with higher RI. Complex karyotype was the only factor adversely influencing survival at all the timepoints. The inclusion of genetic information yielded 2 risk-categories: high-risk defined by the presence of pathogenic variants (PV) in (TP53/BCOR/IDH1/GATA2/BCORL1) and standard-risk (remainder of the patients) with 3-year post-alloSCT OS of 0% and 64.6%, respectively (P = 0.001). We concluded that while alloSCT was curative in a subset of t-MN patients, outcomes remained poor, specifically in the high-risk category. t-MDS patients, especially those with persistent disease pre-alloSCT were at increased risk of relapse. Disease-related factors at t-MN diagnosis were the most prognostic of post-alloSCT survival; utility of factors available later in the course, was incremental.

DOI: https://doi.org/10.1038/s41409-023-01970-0
Nat Commun. 2023 Apr 05. 14(1): 1739

Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.

Yanling Liu, Jonathon Klein, Richa Bajpai, Li Dong, Quang Tran, Pandurang Kolekar, Jenny L Smith, Rhonda E Ries, Benjamin J Huang, Yi-Cheng Wang, Todd A Alonzo, Liqing Tian, Heather L Mulder, Timothy I Shaw, Jing Ma, Michael P Walsh, Guangchun Song, Tamara Westover, Robert J Autry, Alexander M Gout, David A Wheeler, Shibiao Wan, Gang Wu, Jun J Yang, William E Evans, Mignon Loh, John Easton, Jinghui Zhang, Jeffery M Klco, Soheil Meshinchi, Patrick A Brown, Shondra M Pruett-Miller, Xiaotu Ma.

Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.

DOI: https://doi.org/10.1038/s41467-023-37438-4
Genes Dis. 2023 Jan;10(1): 22-25

Pivotal role of cytosolic phospholipase PLA2G4A in the pathogenesis of FLT3-ITD-mutated acute myeloid leukemia.

Wen-Jing Lai, Fan Chen, Lingling Shu, Xin-Ming Yang, Jimin Yuan, Jing-Bo Xu, Anskar Yu-Hung Leung, Bai-Liang He.

DOI: https://doi.org/10.1016/j.gendis.2022.02.002
Front Oncol. 2023 ;13 1095870

Real-world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption.

Sarah Morin, Federica Giannotti, Anne-Claire Mamez, Amandine Pradier, Stavroula Masouridi-Levrat, Federico Simonetta, Yves Chalandon.

  Sorafenib significantly improves survival of FLT3-ITD mutated AML patients when used as a post-allogeneic HSCT maintenance. Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation. The aim of our analysis was to evaluate the real-world experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. We conducted a single-center retrospective study on 30 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2017 and 2020 and who received sorafenib maintenance. 26 patients (87%) experienced toxicities leading to dose reduction (n=9) or direct interruption (n=17). Average time on sorafenib was 125 days (range 1-765). Most common toxicities were skin, gastrointestinal, and hematologic. Among patients who had a dose reduction, 4 eventually interrupted the drug and 5 were able to continue. Among patients who interrupted sorafenib because of toxicities, 7 were re-challenged with good tolerance in 3 cases. Overall, 18 patients (60% of the entire cohort) definitively discontinued sorafenib because of toxicities. 14 patients were thereafter switched to midostaurin. Importantly, with a median follow-up of 12 months, the median overall survival was not reached suggesting a positive impact of sorafenib maintenance despite the high rates of treatment interruption. In conclusion, our real-world analysis reveals high rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT. Interestingly, our results suggest the feasibility of re-challenging with sorafenib and/or of switching to other maintenance approaches in case of intolerance.

Keywords:  HSCT = hematopoietic stem cell transplant; acute myeloid leukemia; drug toxicity and adverse effect; maintenance; sorafenib

DOI:  https://doi.org/10.3389/fonc.2023.1095870
Blood. 2023 Apr 06. 141(14): 1653-1655

Silencing with SAFB: a new role for HOXA9 in AML.

Aniruddha J Deshpande, Nan Zhu.

DOI: https://doi.org/10.1182/blood.2022019244
Haematologica. 2023 Apr 06.

Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival.

Jesse M Tettero, Lok Lam Ngai, Costa Bachas, Dimitri A Breems, Thomas Fischer, Bjorn T Gjertsen, Patrycja Gradowska, Laimonas Griskevicius, Jeroen J W M Janssen, Gunnar Juliusson, Johan Maertens, Markus G Manz, Thomas Pabst, Jakob Passweg, Kimmo Porkka, Peter J M Valk, Bob Löwenberg, Gert J Ossenkoppele, Jacqueline Cloos.

Not available.

DOI: https://doi.org/10.3324/haematol.2022.282639
Blood. 2023 Apr 05. pii: blood.2022018071. [Epub ahead of print]

Human CD34+ hematopoietic stem cell hierarchy: how far are we with its delineation at the most primitive level?

Fernando Anjos-Afonso, Dominique Bonnet.

The ability to isolate and characterize different HSPC (hematopoietic stem/progenitor cell) populations opens avenues to understand how hematopoiesis is regulated during development, homeostasis and regeneration, as well as in age-related conditions such as clonal hematopoiesis and leukemogenesis. Significant progress has been made in the past few decades in determining the composition of the cell types that exist in this system, but the most significant advances have come from mouse studies. However, recent breakthroughs have made significant strides that have enhanced the resolution of the human primitive hematopoietic compartment. Therefore, we aim to review this subject not only from a historical perspective but also to discuss the progress made in the characterization of the human post-natal CD34+ HSC-enriched populations. This approach will enable us to shed light on the potential future translational applicability of human HSCs.

DOI: https://doi.org/10.1182/blood.2022018071
Leukemia. 2023 Apr 06.

What role for somatic mutations in systemic inflammatory and autoimmune diseases associated with myelodysplastic neoplasms and chronic myelomonocytic leukemias?

Lin-Pierre Zhao, Marie Sébert, Arsène Mékinian, Olivier Fain, Marion Espéli, Karl Balabanian, Nicolas Dulphy, Lionel Adès, Pierre Fenaux.

DOI: https://doi.org/10.1038/s41375-023-01890-4
Sci Transl Med. 2023 Apr 05. 15(690): eabk1900

TSTEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models.

Deborah Meyran, Joe Jiang Zhu, Jeanne Butler, Daniela Tantalo, Sean MacDonald, Thu Ngoc Nguyen, Minyu Wang, Niko Thio, Criselle D'Souza, Vicky Mengfei Qin, Clare Slaney, Aaron Harrison, Kevin Sek, Pasquale Petrone, Kevin Thia, Lauren Giuffrida, Andrew M Scott, Rachael L Terry, Ben Tran, Jayesh Desai, H Miles Prince, Simon J Harrison, Paul A Beavis, Michael H Kershaw, Ben Solomon, Paul G Ekert, Joseph A Trapani, Phillip K Darcy, Paul J Neeson.

Patients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8+ memory T cell progenitors that can become either functional stem-like T (TSTEM) cells or dysfunctional T progenitor exhausted (TPEX) cells. To that end, we demonstrated that TSTEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate TSTEM-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, TSTEM-like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4+ T cells during TSTEM-like CAR-T cell production. Adoptive transfer of TSTEM-like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of TSTEM-like CAR-T cells and an increased memory T cell pool. Last, TSTEM-like CAR-T cells and anti-programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8+CAR+ T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated TSTEM-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.

DOI: https://doi.org/10.1126/scitranslmed.abk1900
Haematologica. 2023 Apr 06.

IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia.

Benedetta Fiordi, Valentina Salvestrini, Gabriele Gugliotta, Fausto Castagnetti, Antonio Curti, Daniel E Speiser, Emanuela Marcenaro, Camilla Jandus, Sara Trabanelli.

Chronic Myeloid Leukemia (CML) is a hematologic malignancy associated to an unregulated growth of myeloid cells in Bone Marrow (BM) and Peripheral Blood (PB), characterized by the BCR-ABL1 translocation. Given the known cytokine impairment in the leukemic niche of CML, we investigated the impact of this microenvironmental dysregulation on Innate Lymphoid Cells (ILCs), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that IL-18 and VEGF-A are increased in CML patients' sera and that ILC2s are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2s highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2s are hyper-activated through a tumor-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, we discovered that the pro-tumoral axis involving VEGF-A, IL-18 and ILC2s was disrupted upon Tyrosine Kinase Inhibitors' (TKIs) treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18.

DOI: https://doi.org/10.3324/haematol.2022.282140
Leuk Lymphoma. 2023 Apr 05. 1-13

Patient-reported outcomes from the phase 3 ADMIRAL trial in patients with FLT3-mutated relapsed/refractory AML.

Ellen K Ritchie, David Cella, Francesco Fabbiano, Arnaud Pigneux, Yoshinobu Kanda, Cristina Ivanescu, Bhavik J Pandya, Manasee V Shah.

  Patient-reported outcomes (PROs) can inform treatment selection and assess treatment value in acute myeloid leukemia (AML). We evaluated PROs from the ADMIRAL trial (NCT02421939) in patients with FLT3-mutated relapsed/refractory (R/R) AML. PRO instruments consisted of Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), Functional Assessment of Chronic Illness Therapy-Dyspnea Short Form (FACIT-Dys SF), EuroQoL 5-Dimension 5-Level (EQ-5D-5L), and leukemia treatment-specific symptom questionnaires. Clinically significant effects on fatigue were observed with gilteritinib during the first two treatment cycles. Shorter survival was associated with clinically significant worsening of BFI, FACT-Leu, FACIT-Dys SF, and EQ-5D-5L measures. Transplantation and transfusion independence in gilteritinib-arm patients were also associated with maintenance or improvement in PROs. Health-related quality of life remained stable in the gilteritinib arm. Hospitalization had a small but significant effect on patient-reported fatigue. Gilteritinib was associated with a favorable effect on fatigue and other PROs in patients with FLT3-mutated R/R AML.

Keywords:  Acute myeloid leukemia; FLT3 inhibitor; fatigue; health-related quality of life

DOI:  https://doi.org/10.1080/10428194.2023.2186731
Leukemia. 2023 Apr 05.

The KMT2A recombinome of acute leukemias in 2023.

C Meyer, P Larghero, B Almeida Lopes, T Burmeister, D Gröger, R Sutton, N C Venn, G Cazzaniga, L Corral Abascal, G Tsaur, L Fechina, M Emerenciano, M S Pombo-de-Oliveira, T Lund-Aho, T Lundán, M Montonen, V Juvonen, J Zuna, J Trka, P Ballerini, H Lapillonne, V H J Van der Velden, E Sonneveld, E Delabesse, R R C de Matos, M L M Silva, S Bomken, K Katsibardi, M Keernik, N Grardel, J Mason, R Price, J Kim, C Eckert, L Lo Nigro, C Bueno, P Menendez, U Zur Stadt, P Gameiro, L Sedék, T Szczepański, A Bidet, V Marcu, K Shichrur, S Izraeli, H O Madsen, B W Schäfer, S Kubetzko, R Kim, E Clappier, H Trautmann, M Brüggemann, P Archer, J Hancock, J Alten, A Möricke, M Stanulla, J Lentes, A K Bergmann, S Strehl, S Köhrer, K Nebral, M N Dworzak, O A Haas, C Arfeuille, A Caye-Eude, H Cavé, R Marschalek.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

DOI: https://doi.org/10.1038/s41375-023-01877-1
Bone Marrow Transplant. 2023 Apr 04.

The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia.

Fiona Fernando, Andrew J Innes, Simone Claudiani, Angharad Pryce, Chloe Hayden, Jenny Byrne, Paolo Gallipoli, Mhairi Copland, Jane F Apperley, Dragana Milojkovic.

DOI: https://doi.org/10.1038/s41409-023-01975-9
Nat Metab. 2023 Apr 03.

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.

Alanna C Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S A Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser.

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

DOI: https://doi.org/10.1038/s42255-023-00771-5