bims-tremyl 2023-01-22 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2023–01–22
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Dual mTORC1/2 inhibition synergistically enhances AML cell death in combination with the BCL2 antagonist venetoclax.
SWI/SNF blockade disrupts PU.1-directed enhancer programs in normal hematopoietic cells and acute myeloid leukemia.
Immunophenotypical profiling of myeloid neoplasms with erythroid predominance using mass cytometry (CyTOF).
Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial.
Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.
Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia.
Novel high-risk acute myeloid leukemia subgroup with ERG amplification and Biallelic loss of TP53.
Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry.
A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia.
Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.
Experimental drugs in clinical trials for acute myeloid leukemia: Innovations, trends and opportunities.
T-replete cord transplants give superior outcomes in high risk and relapsed/refractory paediatric myeloid malignancy.
A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic datasets.
TP53 mutations and variant allele frequency in myelodysplastic syndromes with del(5q): a Mayo-Moffitt study of 156 informative cases.
A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation.
Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition.
Flt3- and Tie2-Cre tracing identifies regeneration in sepsis from multipotent progenitors but not hematopoietic stem cells.
CDK7 inhibition induces apoptosis in acute myeloid leukemia cells and exerts synergistic antileukemic effects with azacitidine in vitro and in vivo.
Biologic Features and Clinical Outcomes in Newly Diagnosed Myelodysplastic Syndrome with KMT2A rearrangements.
Juvenile myelomonocytic leukemia; moving forward.
Clinical and molecular response of acute myeloid leukemia harboring non-canonical FLT3 N676K driver mutations to contemporary FLT3 inhibitors.
Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.
3q26.2/MECOM Rearrangements by Pericentric Inv(3): Diagnostic Challenges and Clinicopathologic Features.
Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia.
Aging alters the cell cycle control and mitogenic signaling responses of human hematopoietic stem cells.
Genomics of PDGFR-rearranged hypereosinophilic syndrome.
BTG1 mutation yields supercompetitive B cells primed for malignant transformation.
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
Acetyl-CoA metabolism in cancer.
Impact of the HLA Immunopeptidome on Survival of Leukemia Patients After Unrelated Donor Transplantation.
Cost-effectiveness analysis of gemtuzumab ozogamicin for the treatment of de novo CD33-positive Acute Myeloid Leukaemia (AML) in Italy.
Role of allotransplantation in older patients with AML.

Clin Cancer Res. 2023 Jan 18. pii: CCR-22-2729. [Epub ahead of print]

Dual mTORC1/2 inhibition synergistically enhances AML cell death in combination with the BCL2 antagonist venetoclax.

Toshihisa Satta, Lin Li, Sri Lakshmi Chalasani, Xiaoyan Hu, Jewel Nkwocha, Kanika Sharma, Maciej Kmieciak, Mohamed Rahmani, Liang Zhou, Steven Grant.

PURPOSE: Acute myeloid leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition.
METHODS: Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells over-expressing MCL-1, constitutively active AKT, BAK and/or BAX knock-out, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models.
RESULTS: Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor Rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 down-regulation and dependent upon MCL-1 downregulation and BAK/BAX up-regulation as MCL-1 overexpression and BAX/BAK knock out abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax- resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased anti-leukemia effects in in vivo xenograft and PDX models.
CONCLUSIONS: The venetoclax/INK128 regimen exerts significant anti-leukemic activity in various preclinical models through mechanisms involving MCL-1 down-regulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax resistant AML cells, and in in vivoAML models. Further investigation of this strategy appears warranted.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2729
Cancer Res. 2023 Jan 20. pii: CAN-22-2129. [Epub ahead of print]

SWI/SNF blockade disrupts PU.1-directed enhancer programs in normal hematopoietic cells and acute myeloid leukemia.

Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, Daniel Lacorazza, Rachel E Rau, H Courtney Hodges.

In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of non-tumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2129
Cytometry A. 2023 Jan 17.

Immunophenotypical profiling of myeloid neoplasms with erythroid predominance using mass cytometry (CyTOF).

Abdul-Habib Maag, Helen Swanton, Miriam Kull, Naidu M Vegi, Michaela Feuring.

   BACKGROUND: Acute erythroid leukemia (AEL) is a disease continuum between Myelodysplastic syndrome (MDS) and Acute myeloid leukemia (AML) with the cellular hallmark of uncontrolled proliferation and impaired differentiation of erythroid progenitor cells. First described by Giovanni di Guglielmo in 1917 AEL accounts for less than 5% of all de novo AML cases. There have been efforts to characterize AEL at a molecular level, describing recurrent alterations in TP53, NPM1 and FLT3 genes. A genomic analysis of AEL cases confirmed its complexity. Despite these advances, the biology underlying erythroid proliferations remains unclear and the prognosis is dismal with a median survival of only 3 months for pure erythroid leukemia (PEL). Marker combinations suitable for the identification and characterization of leukemic stem cell (LSC) candidates, monitoring measurable residual disease (MRD) during chemotherapy treatment and the development of innovative targeted therapies are missing.
METHODS: Here, we developed a mass cytometry panel for an in-depth characterization of erythroid and myeloid blast cell populations from human AEL bone marrow samples in comparison to other AML subtypes and healthy counterparts. A total of 8 AEL samples were analysed and compared to 28 AML samples from different molecular subtypes, healthy bone marrow counterparts (n=5) and umbilical cord blood (n=6) using high-dimensional mass cytometry.
RESULTS: Identification of erythroid and myeloid blast populations in high-dimensional mass cytometry data enabled a refined view on erythroblast differentiation stages present in AEL erythroid blasts and revealed immunophenotypical profiles specific to AEL. Profiling of phenotypic LSCs revealed aberrant erythroid marker expression in the CD34+ CD38- stem cell compartment. In addition, the identification of novel candidate surface marker combinations and aberrancies might enhance clinical diagnostics of AEL.
CONCLUSIONS: We present a high-parameter mass cytometry approach feasible for immunophenotypical analysis of blast and stem cell populations in myeloid neoplasms with erythroid predominance laying the foundation for more precise experimental approaches in the future. This article is protected by copyright. All rights reserved.

Keywords:  Mass cytometry; acute erythroid leukemia; acute myeloid leukemia

DOI:  https://doi.org/10.1002/cyto.a.24716
Am J Hematol. 2023 Jan 19.

Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial.

Andrew H Wei, Hartmut Döhner, Hamid Sayar, Farhad Ravandi, Pau Montesinos, Hervé Dombret, Dominik Selleslag, Kimmo Porkka, Jun-Ho Jang, Barry Skikne, C L Beach, Thomas Prebet, George Zhang, Alberto Risueño, Manuel Ugidos, Wendy L See, Daniel Menezes, Gail J Roboz.

DOI: https://doi.org/10.1002/ajh.26847
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208176120

Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.

Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, François Lemonnier, Wanda Y Li, Miki S Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, Annick You-Ten, Daniel J Butler, Thorsten Berger, Mark D Minden, Ross L Levine, Cynthia J Guidos, Ari M Melnick, Christopher E Mason, Tak W Mak.

  Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

Keywords:  IDH; TET2; epigenetics; myeloid neoplasm

DOI:  https://doi.org/10.1073/pnas.2208176120
Cancers (Basel). 2023 Jan 05. pii: 352. [Epub ahead of print]15(2):

Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia.

Corentin Orvain, Eduardo Rodríguez-Arbolí, Megan Othus, Brenda M Sandmaier, H Joachim Deeg, Frederick R Appelbaum, Roland B Walter.

  (1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary AML is now considered a diagnostic qualifier rather than a separate disease entity. (2) Methods: To assess the association between clinical history and AML outcomes in the context of allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 759 patients with de novo AML, 115 with AHD AML, and 105 with therapy-related AML who received first allografts while in first or second remission. (3) Results: At the time of HCT, these three cohorts differed significantly regarding many patient and disease-specific characteristics, including age (p < 0.001), gender (p < 0.001), disease risk (p = 0.005), HCT-CI score (p < 0.001), blood count recovery (p = 0.003), first vs. second remission (p < 0.001), remission duration (p < 0.001), measurable residual disease (MRD; p < 0.001), and conditioning intensity (p < 0.001). Relative to patients with de novo AML, relapse rates were similar for patients with AHD (hazard ratio [HR] = 1.07, p = 0.7) and therapy-related AML (HR = 0.86, p = 0.4) after multivariable adjustment, as were relapse-free survival (HR = 1.20, p = 0.2, and HR = 0.89, p = 0.5) and overall survival (HR = 1.19, p = 0.2, and HR = 0.93, p = 0.6). Non-relapse mortality was higher for AHD AML (HR = 1.59, p = 0.047). (4) Conclusions: These data suggest that the clinical history by itself contains limited prognostic value for adults with AML undergoing allografting, supporting the most recent approach to use this information as a diagnostic qualifier rather than a disease entity.

Keywords:  acute myeloid leukemia (AML); allogeneic hematopoietic cell transplantation (HCT); antecedent hematologic disease (AHD); prognostication; therapy-related

DOI:  https://doi.org/10.3390/cancers15020352
Cancer Genet. 2023 Jan 17. pii: S2210-7762(23)00004-2. [Epub ahead of print]272-273 23-28

Novel high-risk acute myeloid leukemia subgroup with ERG amplification and Biallelic loss of TP53.

Cynthia A Schandl, Sandra Mazzoni, Iya Znoyko, Georges J Nahhas, Dongjun Chung, Yanna Ding, Brian Hess, Daynna J Wolff.

  ETS-related gene (ERG) amplification, observed in 4-6% of acute myeloid leukemia (AML), is associated with unfavorable prognosis. To determine coincident effects of additional genomic abnormalities in AML with ERG amplification (ERGamp), we examined 11 ERGamp cases of 205 newly diagnosed AML using chromosomal microarray analysis and next generation sequencing. ERGamp cases demonstrated a distinct pattern of high genetic complexity: loss of 5q, chromothripsis and TP53 loss of function variants. Remarkably, allelic TP53 loss or loss of heterozygosity (LOH) co-occurring with TP53 inactivating mutation dramatically effected ERGamp tumor patient outcome. In the presence of homozygous TP53 loss of function, ERGamp patients demonstrated no response to induction chemotherapy with median overall survival (OS) of 3.8 months (N = 9). Two patients with heterozygous loss of TP53 function underwent alloSCT without evidence of relapse at one year. Similarly, a validation TCGA cohort, 6 of the 8 ERGamp cases with TP53 loss of function demonstrated median OS of 2.5 months. This suggests that with TP53 mutant ERGamp AML, successive loss of the second TP53 allele, typically by 17p deletion or LOH identifies a specific high-risk subtype of AML patients who are resistant to standard induction chemotherapy and need novel approaches to avert the very poor prognosis.

Keywords:  AML; ERG; ERGamp; Microarray

DOI:  https://doi.org/10.1016/j.cancergen.2023.01.004
Cancers (Basel). 2023 Jan 10. pii: 438. [Epub ahead of print]15(2):

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry.

Claudia Sargas, Rosa Ayala, María José Larráyoz, María Carmen Chillón, Estrella Carrillo-Cruz, Cristina Bilbao-Sieyro, Esther Prados de la Torre, David Martínez-Cuadrón, Rebeca Rodríguez-Veiga, Blanca Boluda, Cristina Gil, Teresa Bernal, Juan Miguel Bergua, Lorenzo Algarra, Mar Tormo, Pilar Martínez-Sánchez, Elena Soria, Josefina Serrano, Juan Manuel Alonso-Domínguez, Raimundo García-Boyero, María Luz Amigo, Pilar Herrera-Puente, María José Sayas, Esperanza Lavilla-Rubira, Joaquín Martínez-López, María José Calasanz, Ramón García-Sanz, José Antonio Pérez-Simón, María Teresa Gómez-Casares, Joaquín Sánchez-García, Eva Barragán, Pau Montesinos, On Behalf Of Pethema Group.

  Next-Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross-validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS-AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co-occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia-related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

Keywords:  Next–Generation Sequencing; acute myeloid leukemia; clinical validation; cross–validations; genomic classification; mutational profile

DOI:  https://doi.org/10.3390/cancers15020438
Cancer Discov. 2023 Jan 20. OF1

A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia.

A trifunctional natural killer cell engager (NKCE) kills CD123+ acute myeloid leukemia (AML) blasts.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-011
Cancers (Basel). 2023 Jan 12. pii: 484. [Epub ahead of print]15(2):

Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.

Rebecca Anderson, Kristin M Pladna, Nathaniel J Schramm, Frances B Wheeler, Steven Kridel, Timothy S Pardee.

  Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.

Keywords:  leukemia; metabolism; mitochondria; therapy

DOI:  https://doi.org/10.3390/cancers15020484
Expert Opin Investig Drugs. 2023 Jan 20.

Experimental drugs in clinical trials for acute myeloid leukemia: Innovations, trends and opportunities.

Aleksandra Gołos, Joanna Góra-Tybor, Tadeusz Robak.

   INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by many cytogenetic and molecular alterations. Due to better knowledge of the molecular basis of AML, many targeted therapies have been introduced and registered, e.g., FMS-like tyrosine kinase 3 inhibitors, isocitrate dehydrogenase 1/2 mutation inhibitors, and Bcl-2 inhibitor. Despite that, the cure for AML remains an unmet clinical need in most patients.
AREAS COVERED: The review aims to present new, not yet registered drugs for AML. We searched English literature for articles concerning AML, targeted drugs, menin inhibitors, DOT1L, BET, IDH inhibitors, FLT3, Hedgehog inhibitors, Polo-like kinase inhibitors, RNA splicing, and immune therapies via PubMed. Publications from January 2000 to August 2022 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles and Google search. Conference proceedings from the previous five years of The American Society of Hematology, The European Hematology Association, and the American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references.
EXPERT OPINION: For several years, the therapeutic approach in AML has become more individualized. Novel groups of drugs give hope for greater curability. High response rates have agents that restore the activity of the p53 protein. In addition, agents that work independently of a particular mutation seem promising for AML without any known mutation.

Keywords:  DOT1L; FLT3; Hedgehog inhibitor; IDH inhibitor; Polo-like kinase; RNA splicing; acute myeloid leukemia; bromodomain; extraterminal domain; immune therapy; targeted drugs

DOI:  https://doi.org/10.1080/13543784.2023.2171860
Blood Adv. 2023 Jan 17. pii: bloodadvances.2022009253. [Epub ahead of print]

T-replete cord transplants give superior outcomes in high risk and relapsed/refractory paediatric myeloid malignancy.

Claire Horgan, Khushnuma Mullanfiroze, Archana Rauthan, Katharine Patrick, Naeem Akram Butt, Oana Mirci-Danicar, Olya O'Connor, Caroline Louise Furness, Akshay Deshpande, Sarah Lawson, Valerie Broderick, Pamela Evans, Brenda Es Gibson, Wing Roberts, Salah Ali, Sevasti Galani, Amy A Kirkwood, Jelena Jovanovic, Richard James Dillon, Paul Virgo, Beki James, Kanchan Rao, Persis Jal Amrolia, Robert Wynn.

Stem cell transplant (SCT) outcomes in high-risk (HR) and relapsed/refractory (R/R) paediatric acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) have been poor historically. Cord blood allows T-cell replete transplant (TRCB), enabling enhanced graft-versus-leukaemia. We collected data from 367 consecutive patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for paediatric AML/MDS in the UK and Ireland between January 2014 and December 2021. Data was collected about patient's demographics, disease and its treatment including previous transplant, measurable residual disease (MRD) status at transplant, HLA-match, relapse, death, graft versus host disease (GvHD) and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6% and 5.1% respectively in the comparator group (all p <0.001). Within the TRCB cohort, Event Free Survival (EFS) was 64.1%, 50% in MRD positive patients and 79% in MRD negative (p= 0.009). To allow for the imbalance in baseline characteristics, a multivariable analysis was performed: the TRCB cohort had significantly improved EFS (0.57[0.35-0.91], p=0.019), time to relapse (0.46[0.26-0.81), p=0.008), and reduced chronic GVHD (HR 0.28 [95% CI 0.11-0.70]; p=0.007), with some evidence of improved Overall Survival (OS) (0.65[0.39-1.07], p = 0.088). The effect appeared similar regardless of MRD status, (interaction p-value= 0.29). CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.

DOI: https://doi.org/10.1182/bloodadvances.2022009253
Blood. 2023 Jan 18. pii: blood.2022018825. [Epub ahead of print]

A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic datasets.

Caitlyn Vlasschaert, Taralynn Mack, Jonathan Brett Heimlich, Abhishek Niroula, Md Mesbah Uddin, Joshua S Weinstock, Brian Sharber, Alexander J Silver, Yaomin Xu, Michael R Savona, Christopher J Gibson, Matthew B Lanktree, Michael J Rauh, Benjamin L Ebert, Pradeep Natarajan, Siddhartha Jaiswal, Alexander G Bick.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germline variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ~550,000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines prior population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03%/year, which increases to 0.5%/year amongst individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.

DOI: https://doi.org/10.1182/blood.2022018825
Am J Hematol. 2023 Jan 19.

TP53 mutations and variant allele frequency in myelodysplastic syndromes with del(5q): a Mayo-Moffitt study of 156 informative cases.

Farah Fleti, Onyee Chan, Amritpal Singh, Maymona G Abdelmagid, Aref Al-Kali, Michelle A Elliott, Kebede H Begna, James M Foran, Talha Badar, Nandita Khera, Najla H Al Ali, Eric Padron, David A Sallman, Mithun Shah, Devendra Hiwase, Animesh Pardanani, Daniel A Arber, Attilio Orazi, Kaaren K Reichard, Rong He, Rhett P Ketterling, Naseema Gangat, Rami Komrokji, Ayalew Tefferi.

DOI: https://doi.org/10.1002/ajh.26845
Blood Adv. 2023 Jan 20. pii: bloodadvances.2022008591. [Epub ahead of print]

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation.

Chen Wang, Zhaowei Tu, Xiongwei Cai, Weinan Wang, Ashley Kuenzi Davis, Kalpana J Nattamai, Aditi Paranjpe, Phillip Dexheimer, Jianqiang Wu, L Frank Huang, Hartmut Geiger, Gang Huang, Yi Zheng.

As a member of the RUNT domain family core-binding transcription factors, RUNX1 is crucial for multiple stages of hematopoiesis and its mutation can cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). Previous work has established that RUNX1 is involved in the maturation of megakaryocytes and the production of platelets. Recently studies have shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of vWF and CD41 at the apex of the HSC hierarchy, termed MK-HSCs, which can give rise to megakaryocytes without going through the traditional differentiation trajectory from HSC via MPP and MEP. Here, by using Runx1F/FMx1-Cre mouse model we discovered that the MK-HSC to megakaryocyte direct differentiation can happen within one cell division and RUNX1 is an important regulator in the process. Runx1 knockout results in a drastic decrease in platelet counts and a severe defect in the differentiation from MK-HSCs to megakaryocytes. Single cell RNA sequencing (RNAseq) analysis shows that MK-HSCs have a distinct gene expression signature compared with non-MK-HSCs, and Runx1 deletion alters the platelet and megakaryocyte related gene expression in MK-HSCs. Further bulk RNAseq and Cut & Run analyses show that RUNX1 binds to multiple essential megakaryocyte/platelet developmental genes such as Spi1, Selp and Itga2b and regulates their expressions in MK-HSCs. Thus, by modulating the expression of megakaryocyte-related genes, RUNX1 governs the direct differentiation of MK-HSCs to megakaryocytes and platelets.

DOI: https://doi.org/10.1182/bloodadvances.2022008591
Blood Adv. 2023 Jan 17. pii: bloodadvances.2022008019. [Epub ahead of print]

Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition.

Cansu Koyunlar, Emanuele Gioacchino, Disha Vadgama, Hans W J de Looper, Joke Zink, Mariette Ter Borg, Remco Hoogenboezem, Marije Havermans, Mathijs Arnoud Sanders, Eric Bindels, Elaine A Dzierzak, Ivo P Touw, Emma de Pater.

The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) events during embryonic development. The transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because GATA2 haploinsufficiency patients have inborn mutations, prenatal defects are likely to have an influence on disease development. In mice, Gata2 haploinsufficiency (Gata2+/-) reduces the number and the functionality of embryonic hematopoietic stem and progenitor cells (HSPCs) generated through EHT. However, the embryonic HSPC pool is heterogeneous and the mechanisms underlying this defect in Gata2+/- embryos are unclear. Here, we investigated whether Gata2 haploinsufficiency selectively affects a cellular subset undergoing EHT. We show that Gata2+/- HSPCs initiate but cannot fully activate hematopoietic programming during EHT. In addition, due to reduced activity of the endothelial repressor Gfi1b, Gata2+/- HSPCs cannot repress the endothelial identity to complete maturation. Finally, we show that hematopoietic-specific induction of gfi1b can restore HSC production in gata2b-null (gata2b-/-) zebrafish embryos. This study illustrates pivotal roles of Gata2 on the regulation of transcriptional network governing HSPC identity throughout EHT.

DOI: https://doi.org/10.1182/bloodadvances.2022008019
Cell Stem Cell. 2023 Jan 10. pii: S1934-5909(22)00498-2. [Epub ahead of print]

Flt3- and Tie2-Cre tracing identifies regeneration in sepsis from multipotent progenitors but not hematopoietic stem cells.

Ann-Kathrin Fanti, Katrin Busch, Alessandro Greco, Xi Wang, Branko Cirovic, Fuwei Shang, Tamar Nizharadze, Larissa Frank, Melania Barile, Thorsten B Feyerabend, Thomas Höfer, Hans-Reimer Rodewald.

  In response to infections and stress, hematopoiesis rapidly enhances blood and immune cell production. The stage within the hematopoietic hierarchy that accounts for this regeneration is unclear under natural conditions in vivo. We analyzed by differentiation tracing, using inducible Tie2- or Flt3-driven Cre recombinase, the roles of mouse hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). During polymicrobial sepsis, HSCs responded transcriptionally and increased their proliferation and cell death, yet HSC differentiation rates remained at steady-state levels. HSC differentiation was also independent from the ablation of various cellular compartments-bleeding, the antibody-mediated ablation of granulocytes or B lymphocytes, and genetic lymphocyte deficiency. By marked contrast, the fate mapping of MPPs in polymicrobial sepsis identified these cells as a major source for accelerated myeloid cell production. The regulation of blood and immune cell homeostasis by progenitors rather than stem cells may ensure a rapid response while preserving the integrity of the HSC population.

Keywords:  cell ablation; differentiation rates; fate mapping; hematopoiesis; hematopoietic stem cells; infection; inflammation; multipotent progenitors; regeneration; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.stem.2022.12.014
Leuk Lymphoma. 2023 Jan 19. 1-12

CDK7 inhibition induces apoptosis in acute myeloid leukemia cells and exerts synergistic antileukemic effects with azacitidine in vitro and in vivo.

Shuai Zhang, Ru Feng, Jiefei Bai, Shangyong Ning, Xiaodong Xu, Jie Sun, Meng Wu, Hui Liu.

  THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies.

Keywords:  Acute myeloid leukemia; CDK7 inhibitor; apoptosis; azacitidine; c-MYC

DOI:  https://doi.org/10.1080/10428194.2023.2169045
Am J Hematol. 2023 Jan 20.

Biologic Features and Clinical Outcomes in Newly Diagnosed Myelodysplastic Syndrome with KMT2A rearrangements.

Maria Siddiqui, Sergej Konoplev, Ghayas Issa, Hagop Kantarjian, Naval Daver, Farhad Ravandi, Tapan Kadia, Guilin Tang, Sa A Wang, Beenu Thakral, L Jefferey Medeiros, Olga Pozdnyakova, Sherry Pierce, Guillermo Montalban-Bravo, Kelly Chien, Danielle Hammond, Koji Sasaki, Guillermo Garcia-Manero, Robert P Hasserjian.

DOI: https://doi.org/10.1002/ajh.26858
Leukemia. 2023 Jan 20.

Juvenile myelomonocytic leukemia; moving forward.

M Tarek Elghetany, Hélène Cavé, Rita De Vito, Mrinal M Patnaik, Eric Solary, Joseph D Khoury.

DOI: https://doi.org/10.1038/s41375-023-01818-y
Haematologica. 2023 Jan 19.

Clinical and molecular response of acute myeloid leukemia harboring non-canonical FLT3 N676K driver mutations to contemporary FLT3 inhibitors.

Gregory W Roloff, Frank Wen, Aubrianna Ramsland, Andrew S Artz, Satyajit Kosuri, Wendy Stock, Olatoyosi Odenike, Richard A Larson, Hongtao Liu, Lucy A Godley, Michael J Thirman, Anand A Patel, Christopher K Daugherty, Adam S DuVall, Mariam T Nawas, Emily Dworkin, Geoffrey D Wool, Sandeep Gurbuxani, Carrie Fitzpatrick, Jeremy P Segal, Peng Wang, Michael W Drazer.

Not available.

DOI: https://doi.org/10.3324/haematol.2022.282148
Nat Med. 2023 Jan 19.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Timothy A Yap, Naval Daver, Mikhila Mahendra, Jixiang Zhang, Carlos Kamiya-Matsuoka, Funda Meric-Bernstam, Hagop M Kantarjian, Farhad Ravandi, Meghan E Collins, Maria Emilia Di Francesco, Ecaterina E Dumbrava, Siqing Fu, Sisi Gao, Jason P Gay, Sonal Gera, Jing Han, David S Hong, Elias J Jabbour, Zhenlin Ju, Daniel D Karp, Alessia Lodi, Jennifer R Molina, Natalia Baran, Aung Naing, Maro Ohanian, Shubham Pant, Naveen Pemmaraju, Prithviraj Bose, Sarina A Piha-Paul, Jordi Rodon, Carolina Salguero, Koji Sasaki, Anand K Singh, Vivek Subbiah, Apostolia M Tsimberidou, Quanyun A Xu, Musa Yilmaz, Qi Zhang, Yuan Li, Christopher A Bristow, Meenakshi B Bhattacharjee, Stefano Tiziani, Timothy P Heffernan, Christopher P Vellano, Philip Jones, Cobi J Heijnen, Annemieke Kavelaars, Joseph R Marszalek, Marina Konopleva.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

DOI: https://doi.org/10.1038/s41591-022-02103-8
Cancers (Basel). 2023 Jan 11. pii: 458. [Epub ahead of print]15(2):

3q26.2/MECOM Rearrangements by Pericentric Inv(3): Diagnostic Challenges and Clinicopathologic Features.

Zhenya Tang, Wei Wang, Su Yang, Hanadi El Achi, Hong Fang, Karen Amelia Nahmod, Gokce A Toruner, Jie Xu, Beenu Thakral, Edward Ayoub, Ghayas C Issa, C Cameron Yin, M James You, Roberto N Miranda, Joseph D Khoury, L Jeffrey Medeiros, Guilin Tang.

  MECOM rearrangement (MECOM-R) resulting from 3q26.2 aberrations is often associated with myeloid neoplasms and inferior prognosis in affected patients. Uncommonly, certain 3q26.2/MECOM-R can be subtle/cryptic and consequently overlooked by karyotyping. We identified 17 acute myeloid leukemia (AML) patients (male/female: 13/4 with a median age of 67 years, range 42 to 85 years) with a pericentric inv(3) leading to MECOM-R, with breakpoints at 3p23 (n = 11), 3p25 (n = 3), 3p21 (n = 2) and 3p13 (n = 1) on 3p and 3q26.2 on 3q. These pericentric inv(3)s were overlooked by karyotyping initially in 16 of 17 cases and later detected by metaphase FISH analysis. Similar to the patients with classic/paracentric inv(3)(q21q26.2), patients with pericentric inv(3) exhibited frequent cytopenia, morphological dysplasia (especially megakaryocytes), -7/del(7q), frequent NRAS (n = 6), RUNX1 (n = 5) and FLT-3 (n = 4) mutations and dismal outcomes (median overall survival: 14 months). However, patients with pericentric inv(3) more frequently had AML with thrombocytopenia (n = 15, 88%), relative monocytosis in peripheral blood (n = 15, 88%), decreased megakaryocytes (n = 11, 65%), and lower SF3B1 mutation. We conclude that AML with pericentric inv(3) shares some similarities with AML associated with classic/paracentric inv(3)/GATA2::MECOM but also shows certain unique features. Pericentric inv(3)s are often subtle/cryptic by chromosomal analysis. A reflex FISH analysis for MECOM-R is recommended in myeloid neoplasms showing -7/del(7q).

Keywords:  MECOM rearrangement; immunophenotype; mutation profile; pericentric inversion; −7/7q-

DOI:  https://doi.org/10.3390/cancers15020458
Ann Hematol. 2023 Jan 16.

Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia.

Masayuki Aiba, Akio Shigematsu, Toma Suzuki, Takuto Miyagishima.

  Venetoclax (VEN) is now widely used in the treatment of acute myelogenous leukemia (AML) in elderly patients who are not eligible for intensive remission induction therapy. Prolonged myelosuppression, increased incidence of infection, and long duration of hospital stay were major concerns for VEN treatment cases, and we thought that shortening the duration of VEN administration during induction therapy might solve these problems. Thirteen newly diagnosed AML patients who underwent VEN+azacitidine (AZA) induction therapy from March 2021 to June 2022 at Kushiro Rosai Hospital were analyzed retrospectively. The median age was 79 (range, 68-86) years, and 8 of the patients (61.5%) were classified as high risk according to the ELN 2017 risk stratification. Eight patients received VEN for 14 days (VEN14 group), and 5 patients received VEN for 28 days (VEN28 group). The composite complete remission (CRc) rate was 76.9% in total, and the CRc rates in the VEN14 and VEN28 groups were almost the same (75.0% and 80.0%, respectively). The median overall survival (OS) was not reached in the VEN14 group and was 254 days in the VEN28 group. The median event-free survival (EFS) was not reached in the VEN14 group and was 178 days in the VEN28 group. The VEN14 group might have a possibility to reduce febrile neutropenia (37.5% vs. 80%) and reduce the duration of hospital stay (median, 21.5 vs. 31 days) compared with the VEN28 group. VEN14 produced the same CRc rate and survival rate, safer profile, and shorter duration of hospital stay than VEN28.

Keywords:  Acute myeloid leukemia; Myelosuppression; Short duration; Venetoclax

DOI:  https://doi.org/10.1007/s00277-023-05102-y
Blood. 2023 Jan 18. pii: blood.2022017174. [Epub ahead of print]

Aging alters the cell cycle control and mitogenic signaling responses of human hematopoietic stem cells.

Colin A Hammond, Si Wei Wu, Fangwu Wang, Margarita E MacAldaz, Connie J Eaves.

Human hematopoietic stem cells (HSCs), like their counterparts in mice, comprise a functionally and molecularly heterogeneous population of cells throughout life that, collectively, maintain required outputs of mature blood cellsunder homeostatic conditions. An early developmental change in the HSC population in both species includes a postnatal switch from most of these cells existing in a rapidly cycling state and maintenance of a high self-renewal potential to a majority in a quiescent state with an overall reduced self-renewal potential. However, despite the well-established growth factor dependence of HSC proliferation, if and how this mechanism of HSC regulation might be affected by aging has remained poorly understood. To address this gap, we isolated highly HSC-enriched CD34+CD38-CD45RA-CD90+CD49f+ ("CD49f+") cells from cord blood and adult bone marrow and mobilized peripheral blood samples obtained from normal humans spanning 7 decades of age and then measured their functional and molecular responses to growth-factor stimulation in vitro and regenerative activity in vivo in transplanted mice. Initial experiments revealed advancing donor age was accompanied by a significant and progressively delayed proliferative response but not the altered mature cell outputs seen in normal older individuals. Importantly, subsequent dose-response analyses revealed an age-associated reduction in the growth-factor stimulated proliferation of CD49f+ cells mediated by reduced intrinsic activation of AKT and altered cell-cycle entry and progression. These findings identify a new intrinsic, pervasive, and progressive aging-related alteration in the biological and signaling mechanisms required to drive the proliferation of very primitive normal human hematopoietic cells.

DOI: https://doi.org/10.1182/blood.2022017174
Blood Adv. 2023 Jan 18. pii: bloodadvances.2022009061. [Epub ahead of print]

Genomics of PDGFR-rearranged hypereosinophilic syndrome.

Esther Rheinbay, Meifang Qi, Juliette Bouyssou, Andrew J Oler, Lauren Thumm, Michelle Makiya, Irina Maric, Amy D Klion, Andrew A Lane.

DOI: https://doi.org/10.1182/bloodadvances.2022009061
Science. 2023 Jan 20. 379(6629): eabj7412

BTG1 mutation yields supercompetitive B cells primed for malignant transformation.

Coraline Mlynarczyk, Matt Teater, Juhee Pae, Christopher R Chin, Ling Wang, Theinmozhi Arulraj, Darko Barisic, Antonin Papin, Kenneth B Hoehn, Ekaterina Kots, Jonatan Ersching, Arnab Bandyopadhyay, Ersilia Barin, Hui Xian Poh, Chiara M Evans, Amy Chadburn, Zhengming Chen, Hao Shen, Hannah M Isles, Benedikt Pelzer, Ioanna Tsialta, Ashley S Doane, Huimin Geng, Muhammad Hassan Rehman, Jonah Melnick, Wyatt Morgan, Diu T T Nguyen, Olivier Elemento, Michael G Kharas, Samie R Jaffrey, David W Scott, George Khelashvili, Michael Meyer-Hermann, Gabriel D Victora, Ari Melnick.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

DOI: https://doi.org/10.1126/science.abj7412
Sci Transl Med. 2023 Jan 18. 15(679): eabq6288

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Katharina M Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F Tardiff, Baolong Su, Kevin J Williams, Steven J Bensinger, Chee Yeun Chung, Christian E Badr.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.

DOI: https://doi.org/10.1126/scitranslmed.abq6288
Nat Rev Cancer. 2023 Jan 19.

Acetyl-CoA metabolism in cancer.

David A Guertin, Kathryn E Wellen.

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

DOI: https://doi.org/10.1038/s41568-022-00543-5
J Clin Oncol. 2023 Jan 20. JCO2201229

Impact of the HLA Immunopeptidome on Survival of Leukemia Patients After Unrelated Donor Transplantation.

Pietro Crivello, Esteban Arrieta-Bolaños, Meilun He, Tao Wang, Stephanie Fingerson, Shahinaz M Gadalla, Sophie Paczesny, Steven G E Marsh, Stephanie J Lee, Stephen R Spellman, Yung-Tsi Bolon, Katharina Fleischhauer.

PURPOSE: Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we tested this concept in HLA-A, -B, and -C disparities after single class I HLA-mismatched UD-HCT.
PATIENTS AND METHODS: We studied 2,391 single class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 for acute leukemia or myelodysplastic syndromes. Hierarchical clustering of experimentally determined peptide-binding motifs (PBM) was used as a proxy for immunopeptidome divergence of HLA-A, -B, or -C disparities, allowing us to classify 1,629/2,391 (68.1%) of the HLA-mismatched UD-HCT as PBM-matched or PBM-mismatched. Risks associated with PBM-matching status were assessed by Cox proportional hazards models, with overall survival (OS) as the primary end point.
RESULTS: Relative to full matches, bidirectional or unidirectional PBM mismatches in graft-versus-host (GVH) direction (PBM-GVH mismatches, 60.7%) were associated with significantly lower OS (hazard ratio [HR], 1.48; P < .0001), while unidirectional PBM mismatches in host-versus-graft direction or PBM matches (PBM-GVH matches, 39.3%) were not (HR, 1.13; P = .1017). PBM-GVH mismatches also had significantly lower OS than PBM-GVH matches in direct comparison (HR, 1.32; P = .0036). The hazards for transplant-related mortality and acute and chronic graft-versus-host disease but not relapse increased stepwise from full HLA matches to single PBM-GVH matches, and single PBM-GVH mismatches. A webtool for PBM-matching of single class I HLA-mismatched donor-recipient pairs was developed.
CONCLUSION: PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome. These findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.

DOI: https://doi.org/10.1200/JCO.22.01229
BMC Health Serv Res. 2023 Jan 16. 23(1): 36

Cost-effectiveness analysis of gemtuzumab ozogamicin for the treatment of de novo CD33-positive Acute Myeloid Leukaemia (AML) in Italy.

Roberto Cairoli, Gianluca Furneri, Roberto Di Virgilio, Barbara Veggia, Felicetto Ferrara.

   BACKGROUND: Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service.
METHODS: For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results.
RESULTS: In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT).
CONCLUSIONS: If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML.
TRIAL REGISTRATION: Not applicable.

Keywords:  ALFA-0701 study; Acute myeloid leukemia; Cost-effectiveness; Gemtuzumab ozogamicin; Italy

DOI:  https://doi.org/10.1186/s12913-023-09054-x
Blood. 2023 Jan 19. 141(3): 217-218

Role of allotransplantation in older patients with AML.

Arnold Ganser.

DOI: https://doi.org/10.1182/blood.2022018786