bims-tremyl 2023-10-08 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2023–10–08
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.
Cooperative CAR targeting to selectively eliminate AML and minimize escape.
TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.
Distinct and targetable role of calcium-sensing receptor in leukaemia.
Stressing the stem cell in acute myeloid leukemia.
AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.
Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.
European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia.
What is the impact of failing to achieve TKI therapy milestones in chronic myeloid leukemia.
A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.
Deciphering treatment patterns in non-severe/moderate aplastic anemia: an international observational study.
Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.
Correction: Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.
Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis.
TET2 somatic copy number alterations and allelic imbalances in chronic myelomonocytic leukemia.
Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells.
Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.
Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.
Graft-versus-Host Disease Prophylaxis with Post Transplant Cyclophosphamide in Chronic Myeloid Leukemia patients undergoing Allogeneic Hematopoietic Cell Transplant from either an Unrelated or Mismatched Related Donor: a comparative study from the Chr....
Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia.
Deciphering clonal architecture and evolutionary dynamics of secondary acute myeloid leukemia and donor-derived myelodysplastic syndrome using single-cell multi-omics analysis.
BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.
Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia.
Acute leukemia with predominantly myeloid differentiation and TBL1XR1::CSF1R fusion.
Effectiveness of leukapheresis on early survival in acute myeloid leukemia: An observational propensity score matching cohort study.
Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: a CIBMTR analysis.
Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients.
DDX41: here, there…and everywhere.
Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.
Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
Management of Advanced Systemic Mastocytosis and Associated Myeloid Neoplasms.

Br J Haematol. 2023 Oct 02.

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

Frédéric Baron, Arnon Nagler, Jacques-Emmanuel Galimard, Jaime Sanz, Jurjen Versluis, Edouard Forcade, Patrice Chevallier, Anne Sirvent, Chloe Anthias, Jürgen Kuball, Sabine Furst, Alessandro Rambaldi, Jorge Sierra, Peter A von dem Borne, Maria Pilar Gallego Hernanz, Thomas Cluzeau, Stephen Robinson, Anna Maria Raiola, Hélène Labussière-Wallet, Jenny L Byrne, Jean-Valère Malfuson, Annalisa Ruggeri, Mohamad Mohty, Fabio Ciceri.

  We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Keywords:  AML; acute myeloid leukaemia; cord blood transplantation; de novo; secondary

DOI:  https://doi.org/10.1111/bjh.19130
Cancer Cell. 2023 Oct 04. pii: S1535-6108(23)00326-4. [Epub ahead of print]

Cooperative CAR targeting to selectively eliminate AML and minimize escape.

Sascha Haubner, Jorge Mansilla-Soto, Sarah Nataraj, Friederike Kogel, Qing Chang, Elisa de Stanchina, Michael Lopez, Mei Rosa Ng, Kathryn Fraser, Marion Subklewe, Jae H Park, Xiuyan Wang, Isabelle Rivière, Michel Sadelain.

  Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.

Keywords:  CAR T cell therapy; ICAHT; IF-BETTER gate; acute myeloid leukemia; chimeric antigen receptor; combinatorial targeting; cooperative CAR; hematotoxicity; off-target toxicity; on-target toxicity

DOI:  https://doi.org/10.1016/j.ccell.2023.09.010
Nat Commun. 2023 Oct 04. 14(1): 6185

TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.

Elizabeth Heyes, Anna S Wilhelmson, Anne Wenzel, Gabriele Manhart, Thomas Eder, Mikkel B Schuster, Edwin Rzepa, Sachin Pundhir, Teresa D'Altri, Anne-Katrine Frank, Coline Gentil, Jakob Woessmann, Erwin M Schoof, Manja Meggendorfer, Jürg Schwaller, Torsten Haferlach, Florian Grebien, Bo T Porse.

The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPADM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

DOI: https://doi.org/10.1038/s41467-023-41927-x
Nat Commun. 2023 Oct 06. 14(1): 6242

Distinct and targetable role of calcium-sensing receptor in leukaemia.

Raquel S Pereira, Rahul Kumar, Alessia Cais, Lara Paulini, Alisa Kahler, Jimena Bravo, Valentina R Minciacchi, Theresa Krack, Eric Kowarz, Costanza Zanetti, Parimala Sonika Godavarthy, Fabian Hoeller, Pablo Llavona, Tabea Stark, Georg Tascher, Daniel Nowak, Eshwar Meduri, Brian J P Huntly, Christian Münch, Francesco Pampaloni, Rolf Marschalek, Daniela S Krause.

Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, β-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.

DOI: https://doi.org/10.1038/s41467-023-41770-0
Haematologica. 2023 Oct 05.

Stressing the stem cell in acute myeloid leukemia.

Gautam Borthakur.

Not available.

DOI: https://doi.org/10.3324/haematol.2023.283919
bioRxiv. 2023 Sep 23. pii: 2023.09.21.558911. [Epub ahead of print]

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.

Ece Canan Sayitoglu, Bogdan A Luca, Allison P Boss, Benjamin Craig Thomas, Robert Arthur Freeborn, Molly J Uyeda, Pauline P Chen, Yusuke Nakauchi, Colin Waichler, Norman Lacayo, Rosa Bacchetta, Ravindra Majeti, Andrew J Gentles, Alma-Martina Cepika, Maria Grazia Roncarolo.

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4 + T cells. Single-cell RNA-seq of primary AML samples and CD4 + T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 + T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro . Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1 , a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primary ex vivo -isolated CD8 + T cells in vitro , and engineered CD4 + T cells in vitro and in vivo . Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survival in vivo .
SIGNIFICANCE: AML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulate ICAM1 that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination.
GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.1101/2023.09.21.558911
Res Sq. 2023 Sep 22. pii: rs.3.rs-3315059. [Epub ahead of print]

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

Jeffery Klco, Melvin Thomas Iii, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke.

MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1 , however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga- deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.

DOI: https://doi.org/10.21203/rs.3.rs-3315059/v1
Leukemia. 2023 Oct 04.

European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia.

Nicholas C P Cross, Thomas Ernst, Susan Branford, Jean-Michel Cayuela, Michael Deininger, Alice Fabarius, Dennis Dong Hwan Kim, Katerina Machova Polakova, Jerald P Radich, Rüdiger Hehlmann, Andreas Hochhaus, Jane F Apperley, Simona Soverini.

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.

DOI: https://doi.org/10.1038/s41375-023-02048-y
Leukemia. 2023 Oct 05.

What is the impact of failing to achieve TKI therapy milestones in chronic myeloid leukemia.

Hagop M Kantarjian.

DOI: https://doi.org/10.1038/s41375-023-02053-1
Nat Cancer. 2023 Oct 02.

A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.

Eirini Giannakopoulou, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Yingqian Li, Terhi Karpanen, Tetsuichi Yoshizato, Even H Rustad, Morten Milek Nielsen, Ravi Chand Bollineni, Trung T Tran, Marina Delic-Sarac, Thea Johanne Gjerdingen, Karolos Douvlataniotis, Maarja Laos, Muhammad Ali, Amy Hillen, Stefania Mazzi, Desmond Wai Loon Chin, Adi Mehta, Jeppe Sejerø Holm, Amalie Kai Bentzen, Marie Bill, Marieke Griffioen, Tobias Gedde-Dahl, Sören Lehmann, Sten Eirik W Jacobsen, Petter S Woll, Johanna Olweus.

Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCRFLT3D/Y). TCRFLT3D/Y-redirected T cells selectively eliminated primary human AML cells harboring the FLT3D835Y mutation in vitro and in vivo. TCRFLT3D/Y cells rejected both CD34+ and CD34- AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34+ AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.

DOI: https://doi.org/10.1038/s43018-023-00642-8
Leukemia. 2023 Oct 04.

Deciphering treatment patterns in non-severe/moderate aplastic anemia: an international observational study.

Bruno Fattizzo, Carmelo Gurnari, Giulio Cassanello, Marta Bortolotti, Hussein Awada, Sabrina Giammarco, Dario Consonni, Simona Sica, Shreyans Gandhi, Roochi Trikha, Joanna Large, Sarah Salter, Jaroslaw P Maciejewski, Wilma Barcellini, Austin G Kulasekararaj.

Non-severe aplastic anemia is a rare bone marrow failure disorder characterized by variable degrees and combination of cytopenias, with limited data on management and outcome. We describe a large multicentric series of 259 patients, focusing on clinical and molecular features, treatment, evolution, and survival. The majority required treatment with cyclosporine (CyA) alone (N = 84) or in combination with anti-thymocyte globulin (ATG,44) or eltrombopag (20), eltrombopag alone (10), or others (25) including androgens. Similar outcomes were observed across different strategies, with a 6-month overall response rate of 73% for CyA, 74% for ATG plus CyA, 68% for CyA plus eltrombopag, 87% for eltrombopag, and 79% for others. Notably, 56 patients (39%), mainly receiving CyA plus eltrombopag, achieved a trilineage response (p = 0.02). Progression to myeloid neoplasms was limited (8%) and not related to mutational status. Hemolytic PNH developed in 10% of cases, being predicted by detection of small clones at diagnosis. Survival was negatively impacted by age, male gender, LDH, platelets/erythrocyte transfusion need, and somatic mutations by NGS, and positively by higher neutrophils at diagnosis, PNH clones, and trilineage response at 6 and 12 months. Multivariable analysis confirmed the detrimental role of age and the favorable association with PNH clone and trilineage response at 6 months.

DOI: https://doi.org/10.1038/s41375-023-02047-z
Leuk Res. 2023 Sep 20. pii: S0145-2126(23)00655-0. [Epub ahead of print]134 107390

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.

Tamanna Haque, Felix López Cadenas, Blanca Xicoy, Ana Alfonso-Pierola, Uwe Platzbecker, Irit Avivi, Andrew M Brunner, Jöerg Chromik, Daniel Morillo, Manish R Patel, Jose Falantes, Heather A Leitch, Ulrich Germing, Meir Preis, Laurie Lenox, Josh Lauring, Regina J Brown, Anna Kalota, Jaydeep Mehta, Friederike Pastore, Junchen Gu, Pankaj Mistry, David Valcárcel.

  Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Keywords:  Myelodysplastic Syndromes; Phase 1 Study; Protein Arginine Methyltransferase 5 Inhibitor

DOI:  https://doi.org/10.1016/j.leukres.2023.107390
Leukemia. 2023 Oct 03.

Correction: Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.

Ekaterina Jahn, Maral Saadati, Pierre Fenaux, Marco Gobbi, Gail J Roboz, Lars Bullinger, Pavlo Lutsik, Anna Riedel, Christoph Plass, Nikolaus Jahn, Claudia Walter, Karlheinz Holzmann, Yong Hao, Sue Naim, Nicholas Schreck, Julia Krzykalla, Axel Benner, Harold N Keer, Mohammad Azab, Konstanze Döhner, Hartmut Döhner.

DOI: https://doi.org/10.1038/s41375-023-02017-5
Leukemia. 2023 Oct 04.

Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis.

Dieter Tulkens, Marthe Boelens, Thomas Naert, Marjolein Carron, Suzan Demuynck, Sylviane Dewaele, Gert Van Isterdael, David Creytens, Tim Pieters, Steven Goossens, Pieter Van Vlierberghe, Kris Vleminckx.

CRISPR-mediated simultaneous targeting of candidate tumor suppressor genes in Xenopus tropicalis allows fast functional assessment of co-driver genes for various solid tumors. Genotyping of tumors that emerge in the mosaic mutant animals rapidly exposes the gene mutations under positive selection for tumor establishment. However, applying this simple approach to the blood lineage has not been attempted. Multiple hematologic malignancies have mutations in EZH2, encoding the catalytic subunit of the Polycomb Repressive Complex 2. Interestingly, EZH2 can act as an oncogene or a tumor suppressor, depending on cellular context and disease stage. We show here that mosaic CRISPR/Cas9 mediated ezh2 disruption in the blood lineage resulted in early and penetrant acute myeloid leukemia (AML) induction. While animals were co-targeted with an sgRNA that induces notch1 gain-of-function mutations, sequencing of leukemias revealed positive selection towards biallelic ezh2 mutations regardless of notch1 mutational status. Co-targeting dnm2, recurrently mutated in T/ETP-ALL, induced a switch from myeloid towards acute T-cell leukemia. Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.

DOI: https://doi.org/10.1038/s41375-023-02052-2
Leuk Res. 2023 Sep 20. pii: S0145-2126(23)00656-2. [Epub ahead of print]134 107391

TET2 somatic copy number alterations and allelic imbalances in chronic myelomonocytic leukemia.

Mark Gurney, Patricia T Greipp, Troy Gliem, Ryan Knudson, Aref Al-Kali, Naseema Gangat, Terra Lasho, Abhishek A Mangaonkar, Christy M Finke, Mrinal M Patnaik.



Keywords:  Chromosomal Microarray; Chronic Myelomonocytic Leukemia; Classification; Epigenetic; Myelodysplastic Neoplasm

DOI:  https://doi.org/10.1016/j.leukres.2023.107391
Cancer Lett. 2023 Sep 26. pii: S0304-3835(23)00358-0. [Epub ahead of print]575 216407

Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells.

Jin Wen, Ying Chen, Chenxi Liao, Xiao Ma, Mengyuan Wang, Qian Li, Di Wang, Yingnan Li, Xiaolan Zhang, Lei Li, Hao Zhou, Jing Zou, Lingbo Liu, Danyue Peng.

  Most patients with acute myeloid leukemia (AML) relapse eventually because of the inability to effectively eliminate leukemia stem cells (LSCs), prompting the search of new therapies to eradicate LSCs. Our previous study demonstrated that miR-34c-5p promotes the clearance of LSCs in an AML mouse model, highlighting its potential as a therapeutic target for eradicating LSCs, but the effective delivery of miR-34c-5p to LSCs remains a great challenge. Here, we employed simultaneous two-step modifications to engineer mesenchymal stem cells (MSCs) and MSC-derived exosomes to create exosomes overexpressing the fused protein lysosome-associated membrane protein 2-interleukin 3 (Lamp2b-IL3) and hematopoietic cell E-selectin/L-selectin ligand (HCELL), and demonstrated that the engineered exosomes exhibited an enhanced ability for bone marrow homing and selective targeting of LSCs. Additionally, using a humanized AML mouse model, we confirmed that the engineered exosomes, loaded with miR-34c-5p, could selectively promote eradication of LSCs and impede the AML development in vivo. In summary, we successfully designed an effective delivery system and provided new insights into the development of novel therapies for delivering miRNA or other molecules to LSCs with greater cellular targeting specificity.

Keywords:  CD123; CD44 fucosylation; Engineered exosomes; Leukemia stem cells; Mesenchymal stem cells

DOI:  https://doi.org/10.1016/j.canlet.2023.216407
Nat Cancer. 2023 Oct 02.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Nora Liebers, Peter-Martin Bruch, Tobias Terzer, Miguel Hernandez-Hernandez, Nagarajan Paramasivam, Donnacha Fitzgerald, Heidi Altmann, Tobias Roider, Carolin Kolb, Mareike Knoll, Angela Lenze, Uwe Platzbecker, Christoph Röllig, Claudia Baldus, Hubert Serve, Martin Bornhäuser, Daniel Hübschmann, Carsten Müller-Tidow, Friedrich Stölzel, Wolfgang Huber, Axel Benner, Thorsten Zenz, Junyan Lu, Sascha Dietrich.

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

DOI: https://doi.org/10.1038/s43018-023-00645-5
Leukemia. 2023 Oct 06.

Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

T Ottone, G Silvestrini, R Piazza, S Travaglini, C Gurnari, F Marchesi, A M Nardozza, E Fabiani, E Attardi, L Guarnera, M Divona, P Ricci, M A Irno Consalvo, S Ienzi, R Arcese, A Biagi, L Fiori, M Novello, A Mauriello, A Venditti, L Anemona, M T Voso.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

DOI: https://doi.org/10.1038/s41375-023-02054-0
Transplant Cell Ther. 2023 Sep 30. pii: S2666-6367(23)01573-7. [Epub ahead of print]

Graft-versus-Host Disease Prophylaxis with Post Transplant Cyclophosphamide in Chronic Myeloid Leukemia patients undergoing Allogeneic Hematopoietic Cell Transplant from either an Unrelated or Mismatched Related Donor: a comparative study from the Chr....

Guillermo Ortí, Luuk Gras, Linda Koster, Aleksander Kulagin, Jenny Byrne, Jane F Apperley, Kazimierz Halaburda, Igor Wolfgang Blau, Andrew Clark, Nicolaus Kröger, Laimonas Griskevicius, Kristina Carlson, Matthew Collin, Adrian Bloor, Anna Maria Raiola, Didier Blaise, Mahmoud Aljurf, Lucia López-Corral, Ioanna Sakellari, Yves Beguin, Tomasz Wrobel, Luca de Rosa, Hughes de Lavallade, Patrick J Hayden, Donal McLornan, Yves Chalandon, Ibrahim Yakoub-Agha.

  Outcomes following allogeneic hematopoietic cell transplant (allo-HCT) for Chronic Myeloid Leukemia (CML) with post-transplant cyclophosphamide (PTCy) utilising an unrelated donor (UD) or mismatched related donor (MMRD) remain unknown. We report on a retrospective comparison of PTCy based allo-HCT from an UD, non-PTCy allo-HCT from an UD and PTCy allo-HCT from a MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 to 2019 from an UD with either PTCy or non-PTCy GvHD prophylaxis and MMRD using PTCy. Primary endpoint was GvHD relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43%, 37% and 39% in the non-PTCy UD, PTCy-UD and PTCy MMRD cohorts, respectively (p=0.15). In multivariable analyses, there were no significant differences between the three cohorts regarding OS, PFS, RI and NRM. Factors independently associated with worse OS in the overall cohort were KPS<90 (HR 1.86, 95%CI, 1.41-2.45; p<0.001), older age (HR 1.24, 95%CI, 1.11-1.38; p<0.001) and disease stage (compared to CP1) blast phase HR 2.25, 95% CI, 1.60-3.16; p<0.001, accelerated phase HR 1.63, 95% CI, 1.05-2.54; p=0.03 and CP>2 HR 1.58, 95% CI, 1.15-2.17; p=0.005. These results suggest that allo-HCT in CML utilizing either an UD or MMRD with a PTCy GvHD-based prophylaxis are feasible transplant platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance to closely monitor CML patients and propose transplantation when indicated, when still in CP1.

Keywords:  allogeneic hematopoietic cell transplant; chronic myeloid leukemia; haploidentical donor; posttransplant cyclophosphamide; unrelated donor

DOI:  https://doi.org/10.1016/j.jtct.2023.09.019
Leuk Lymphoma. 2023 Oct 06. 1-9

Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia.

Daria Gaut, Caspian Oliai, Jonathan Boiarsky, Shiliang Zhang, Amandeep Salhotra, Tali Azenkot, Vanessa E Kennedy, Vishesh Khanna, Karla Olmedo Gutierrez, Navika Shukla, Benjamin Moskoff, Gabriel Park, Michelle Afkhami, Anand Patel, Deepa Jeyakumar, Gabriel Mannis, Aaron C Logan, Brian A Jonas, Gary Schiller.

  The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

Keywords:  Acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; consolidation chemotherapy; measurable residual disease

DOI:  https://doi.org/10.1080/10428194.2023.2264426
Am J Hematol. 2023 Oct 04.

Deciphering clonal architecture and evolutionary dynamics of secondary acute myeloid leukemia and donor-derived myelodysplastic syndrome using single-cell multi-omics analysis.

Meng-Ta Sung, Lo-Ho Chen, Ya-Wen Chiang, Jie-Yang Jhuang, Yu-Chen Chang, Gon-Shen Caleb Chen, Ken-Hong Lim.

DOI: https://doi.org/10.1002/ajh.27121
Circulation. 2023 Oct 02.

BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.

Mustafa Yalcinkaya, Wenli Liu, Leigh-Anne Thomas, Malgorzata Olszewska, Tong Xiao, Sandra Abramowicz, Eirini P Papapetrou, Marit Westerterp, Nan Wang, Ira Tabas, Alan R Tall.

   BACKGROUND: Clonal hematopoiesis (CH) has emerged as an independent risk factor for atherosclerotic cardiovascular disease, with activation of macrophage inflammasomes as a potential underlying mechanism. The NLRP3 (NLR family pyrin domain containing 3) inflammasome has a key role in promoting atherosclerosis in mouse models of Tet2 CH, whereas inhibition of the inflammasome product interleukin-1β appeared to particularly benefit patients with TET2 CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]). TET2 is an epigenetic modifier that decreases promoter methylation. However, the mechanisms underlying macrophage NLRP3 inflammasome activation in TET2 (Tet methylcytosine dioxygenase 2) deficiency and potential links with epigenetic modifications are poorly understood.
METHODS: We used cholesterol-loaded TET2-deficient murine and embryonic stem cell-derived isogenic human macrophages to evaluate mechanisms of NLRP3 inflammasome activation in vitro and hypercholesterolemic Ldlr-/- mice modeling TET2 CH to assess the role of NLRP3 inflammasome activation in atherosclerosis.
RESULTS: Tet2 deficiency in murine macrophages acted synergistically with cholesterol loading in cell culture and with hypercholesterolemia in vivo to increase JNK1 (c-Jun N-terminal kinase 1) phosphorylation and NLRP3 inflammasome activation. The mechanism of JNK (c-Jun N-terminal kinase) activation in TET2 deficiency was increased promoter methylation and decreased expression of the JNK-inactivating dual-specificity phosphatase Dusp10. Active Tet1-deadCas9-targeted editing of Dusp10 promoter methylation abolished cholesterol-induced inflammasome activation in Tet2-deficient macrophages. Increased JNK1 signaling led to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3 (BRCA1/BRCA2-containing complex subunit 3). Accelerated atherosclerosis and neutrophil extracellular trap formation (NETosis) in Tet2 CH mice were reversed by holomycin, a BRCC3 deubiquitinase inhibitor, and also by hematopoietic deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex. Human TET2-/- macrophages displayed increased JNK1 and NLRP3 inflammasome activation, especially after cholesterol loading, with reversal by holomycin treatment, indicating human relevance.
CONCLUSIONS: Hypercholesterolemia and TET2 deficiency converge on a common pathway of NLRP3 inflammasome activation mediated by JNK1 activation and BRCC3-mediated NLRP3 deubiquitylation, with potential therapeutic implications for the prevention of cardiovascular disease in TET2 CH.

Keywords:  atherosclerosis; clonal hematopoiesis; extracellular traps; hypercholesterolemia; inflammasomes; neutrophils; phosphorylation

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065344
Nat Commun. 2023 Oct 05. 14(1): 6209

Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia.

Hope Mumme, Beena E Thomas, Swati S Bhasin, Upaasana Krishnan, Bhakti Dwivedi, Pruthvi Perumalla, Debasree Sarkar, Gulay B Ulukaya, Himalee S Sabnis, Sunita I Park, Deborah DeRyckere, Sunil S Raikar, Melinda Pauly, Ryan J Summers, Sharon M Castellino, Daniel S Wechsler, Christopher C Porter, Douglas K Graham, Manoj Bhasin.

Acute myeloid leukemia (AML) microenvironment exhibits cellular and molecular differences among various subtypes. Here, we utilize single-cell RNA sequencing (scRNA-seq) to analyze pediatric AML bone marrow (BM) samples from diagnosis (Dx), end of induction (EOI), and relapse timepoints. Analysis of Dx, EOI scRNA-seq, and TARGET AML RNA-seq datasets reveals an AML blasts-associated 7-gene signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH), which we validate on independent datasets. The analysis reveals distinct clusters of Dx relapse- and continuous complete remission (CCR)-associated AML-blasts with differential expression of genes associated with survival. At Dx, relapse-associated samples have more exhausted T cells while CCR-associated samples have more inflammatory M1 macrophages. Post-therapy EOI residual blasts overexpress fatty acid oxidation, tumor growth, and stemness genes. Also, a post-therapy T-cell cluster associated with relapse samples exhibits downregulation of MHC Class I and T-cell regulatory genes. Altogether, this study deeply characterizes pediatric AML relapse- and CCR-associated samples to provide insights into the BM microenvironment landscape.

DOI: https://doi.org/10.1038/s41467-023-41994-0
Blood. 2023 Oct 05. 142(14): 1253

Acute leukemia with predominantly myeloid differentiation and TBL1XR1::CSF1R fusion.

Jyoti Kumar, Kseniya Petrova-Drus.

DOI: https://doi.org/10.1182/blood.2023021632
J Clin Apher. 2023 Oct 03.

Effectiveness of leukapheresis on early survival in acute myeloid leukemia: An observational propensity score matching cohort study.

Howon Lee, Jay Ho Han, Jae Kwon Kim, Jaeeun Yoo, Hyung Suk Cho, Jae-Ho Yoon, Byung Sik Cho, Hee-Je Kim, Jihyang Lim, Dong Wook Jekarl, Yonggoo Kim.

   BACKGROUND: The association between leukapheresis (LK) as a treatment option for hyperleukocytosis (HL) in patients with acute myeloid leukemia (AML) remains controversial.
METHODS: Data were extracted from the electronic medical record for 2801 patients with AML between April 2009 and December 2019. LK was performed when the leukocyte count was ≥100 × 109 /L at the time initial bone marrow examination.
RESULTS: A comparison between the patients with HL in the non-LK (n = 1579) and LK (n = 208) groups revealed survival probabilities (%) of 93.2% and 90.4% (P = .130) for day 30 (D30), 85.4% and 84.2% (P = .196) for D60, and 83.6% and 80.8% (P = .258) for D90, respectively. After propensity score matching, a comparison between the patients with HL in the non-LK (n = 192) and LK (n = 192) groups revealed survival probabilities (%) of 83.9% and 91.2% (P = .030) for D30, 75.0% and 84.9% (P = .015) for day 60 (D60), and 62.4% and 81.3% (P = .034) for day 90 (D90), respectively. After D150, the observed effect of LK appeared to be mitigated without a survival benefit.
DISCUSSION: LK was associated with improved early survival outcomes at D30, D60, and D90 among patients with AML exhibiting HL. Thus, it may be considered a treatment option for reducing cell mass in such patients.

Keywords:  acute myeloid leukemia; early survival; leukapheresis; propensity-matched study

DOI:  https://doi.org/10.1002/jca.22090
Blood Adv. 2023 Oct 04. pii: bloodadvances.2023011308. [Epub ahead of print]

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: a CIBMTR analysis.

Hemant S Murthy, Mei-Jie Zhang, Karen Chen, Sairah Ahmed, Uday Deotare, Siddhartha Ganguly, Ankit Kansagra, Fotios V Michelis, Taiga Nishihori, Mrinal M Patnaik, Muhammad Bilal Abid, Mahmoud Aljurf, Yasuyuki Arai, Ulrike Bacher, Talha Badar, Sherif M Badawy, Karen Ballen, Minoo Battiwalla, Amer Beitinjaneh, Nelli Bejanyan, Vijaya R Bhatt, Valerie Inez Brown, Rodrigo Martino, Jean-Yves Cahn, Paul Castillo, Jan Cerny, Saurabh Chhabra, Edward A Copelan, Andrew Daly, Bhagirathbhai Dholaria, Miguel Angel Diaz, César O Freytes, Michael R Grunwald, Shahrukh Hashmi, Gerhard C Hildebrandt, Omer Jamy, Jacinth Joseph, Christopher G Kanakry, Nandita Khera, Maxwell M Krem, Yachiyo Kuwatsuka, Hillard M Lazarus, Lazaros J Lekakis, Hongtao Liu, Dipenkumar Modi, Pashna Munshi, Alberto Mussetti, Neil Palmisiano, Sagar S Patel, David A Rizzieri, Sachiko Seo, Mithun Vinod Shah, Akshay Sharma, Melhem M Solh, Scott R Solomon, Matthew L Ulrickson, Celalettin Ustun, Marjolein W M van der Poel, Leo F Verdonck, John L Wagner, Trent P Wang, Baldeep Wirk, Amer M Zeidan, Mark R Litzow, Partow Kebriaei, Christopher S Hourigan, Daniel J Weisdorf, Wael Saber, Mohamed A Kharfan-Dabaja.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with standard conventional chemotherapy. Small observational studies have shown that allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We conducted an analysis of 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007-2018 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Results: Median follow up of survivors was 49 months (range 6-121). 5-year overall survival (OS), disease-free survival (DFS), relapse, and non-relapse (NRM) rates were 51.2% (95% confidence interval [95%CI]: 42.5-59.8%), 44.4% (95%CI: 36.2-52.8%), 32.2% (95%CI: 24.7-40.3%), and 23.3% (95%CI: 16.9-30.4%), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age ≥60 was predictive for inferior OS (hazard ratio [HR]= 2.16, 95% CI 1.35-3.46, p= 0.001), and higher NRM [HR= 2.19, 95% CI 1.13-4.22, p= 0.02]. Remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior OS [HR= 1.87, 95% CI 1.14-3.06, p= 0.01] and DFS [HR= 1.75, 95% CI 1.11-2.76, p= 0.02]. Use of myeloablative conditioning with total body irradiation (TBI) was predictive for improved DFS and reduced risk of relapse. Conclusion: Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, while myeloablative conditioning with TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

DOI: https://doi.org/10.1182/bloodadvances.2023011308
Hemasphere. 2023 Oct;7(10): e957

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients.

Victoria Panagiota, Johanna Franziska Kerschbaum, Olaf Penack, Catarina M Stein, Christopher M Arends, Christian Koenecke, Paulina M Strzelecka, Arnold Kloos, Laura Wiegand, Alina Lasch, Robert Altwasser, Adriane Halik, Razif Gabdoulline, Julia Thomson, Konstantin Weibl, Georg-Nikolaus Franke, Carolina Berger, Justin Hasenkamp, Francis Ayuk, Il-Kang Na, Gernot Beutel, Ulrich Keller, Lars Bullinger, Gerald Georg Wulf, Nicolaus Kröger, Vladan Vucinic, Michael Heuser, Frederik Damm.

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

DOI: https://doi.org/10.1097/HS9.0000000000000957
Blood. 2023 Oct 05. 142(14): 1177-1178

DDX41: here, there…and everywhere.

Christopher R Reilly, Andrew A Lane.

DOI: https://doi.org/10.1182/blood.2023021850
Cell. 2023 Sep 29. pii: S0092-8674(23)01028-0. [Epub ahead of print]

Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.

Zach H Gray, Damayanti Chakraborty, Reuben R Duttweiler, Gulnaz D Alekbaeva, Sedona E Murphy, Kashish Chetal, Fei Ji, Benjamin I Ferman, Madison A Honer, Zhentian Wang, Cynthia Myers, Renhong Sun, H Ümit Kaniskan, Monika Maria Toma, Elena A Bondarenko, John N Santoro, Christopher Miranda, Megan E Dillingham, Ran Tang, Or Gozani, Jian Jin, Tomasz Skorski, Cihangir Duy, Hayan Lee, Ruslan I Sadreyev, Johnathan R Whetstine.

  MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

Keywords:  CTCF; DNA amplification; G9a; H3K9me; KDM3B; KMT2A; MLL; doxorubicin; ecDNA; rearrangements

DOI:  https://doi.org/10.1016/j.cell.2023.09.009
Exp Hematol. 2023 Sep 29. pii: S0301-472X(23)01733-2. [Epub ahead of print]

Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.

Nazanin Karimnia, James Harris, Shen Y Heazlewood, Benjamin Cao, Susan K Nilsson.

  Aging is accompanied by a gradual decline in the function and regenerative capacity of hematopoietic stem cells (HSCs), which leads to increased susceptibility to blood disorders. Recent studies have highlighted the critical role of metabolic regulation in governing the fate and function of HSCs, and alterations in metabolism play a critical role in the age-related changes observed in HSCs. Metabolic processes including glycolysis, mitochondrial function, nutrient sensing and inflammation, profoundly influence the maintenance, self-renewal and differentiation potential of the HSC pool. This review focuses on the metabolic alterations that occur in HSCs during aging and the systemic factors which contribute to HSC metabolic dysregulation, leading to impaired cellular function and reduced regenerative capacity. We highlight the impact of age-associated changes in oxidative stress, mitochondrial dysfunction, nutrient availability and inflammation on HSC metabolism and function. Targeting metabolic pathways and modulating key regulators of metabolism hold promise for reducing age-related HSC dysregulation, thus maintaining functional potential as a path towards healthy aging. Exploiting these metabolic interventions has the potential to improve hemopoietic recovery, enhance immune function and pave the way for novel therapeutic interventions to combat age-related blood disorders.

Keywords:  Aging; autophagy; hematopoietic stem cell; metabolism; mitochondria; niche; nutrients

DOI:  https://doi.org/10.1016/j.exphem.2023.09.006
Immunol Allergy Clin North Am. 2023 Nov;pii: S0889-8561(23)00043-7. [Epub ahead of print]43(4): 723-741

Management of Advanced Systemic Mastocytosis and Associated Myeloid Neoplasms.

Tsewang Tashi, Michael W Deininger.

  Advanced systemic mastocytosis (AdvSM) is a heterogeneous group of disorders characterized by neoplastic mast cell-related organ damage and frequently associated with a myeloid neoplasm. The 3 clinical entities that comprise AdvSM are aggressive SM (ASM), SM-associated hematologic neoplasm, and mast cell leukemia. A gain-of-function KIT D816 V mutation is the primary oncogenic driver found in about 90% of all patients with AdvSM. Midostaurin, an oral multikinase inhibitor with activity against KIT D816V, and avapritinib, an oral selective KIT D816V inhibitor are approved for AdvSM.

Keywords:  Associated hematologic neoplasm; Avapritinib; KIT D816 V; KIT inhibitors; Systemic mastocytosis; Tryptase

DOI:  https://doi.org/10.1016/j.iac.2023.04.009