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Rock hunters, tree huggers and taxi drivers: Books in brief

Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes

Abstract Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). As of May 2023, 107 patients received venetoclax and azacitidine combination at the RP2D. Best response of CR or marrow CR was observed in 29.9% and 50.5% (mOR, 80.4%), respectively. Median OS was 26.0 months, with 1- and 2-year survival estimates of 71.2% and 51.3%, respectively. Among 59 patients with baseline red blood cell and/or platelet transfusion–dependence, 24 (40.7%) achieved transfusion independence on study, including 11 (18.6%) in CR. Fifty-one (49.0%) of 104 evaluable patients achieved HI. Median TTNT excluding transplantation was 13.4 months. Adverse events reflected known safety profiles for venetoclax and azacitidine, including constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%). Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to confirm survival benefit of this combination. This trial was registered at www.clinicaltrials.gov as #NCT02942290.

Characterising the performance of a drone-mounted real-time methane imaging system

Abstract We demonstrate a methane gas imaging system mounted to an unmanned aerial vehicle (UAV) that is shown to perform real-time detection at distances up to 10m whist airborne. Laser diodes that switch between on- and off- resonance with a $${1.6}{{\upmu \hbox {m}}}$$ 1.6 μ m methane absorption line are used to flood-illuminate a scene. The scene is imaged with an infrared InGaAs camera and the differential of the on-resonance and off-resonance back-scatter images are used to reveal the gas distribution. The performance of the system was characterised against a range of back-scatter surfaces, showing promising applicability to realistic gas sensing environments. We demonstrate that the system is capable of detecting a gas concentration of 5000 ppm.metre up to a range of 13.6m.

Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages

Abstract The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

Phenolic compounds and safety of improved and local peanut varieties grown in Burkina Faso

The surprising culprit for the loss of huge swathes of tropical forest

Low counts count after CAR-T for ALL

Robot multi-target high performance grasping detection based on random sub-path fusion

Heat-insoluble cryoglobulin in peripheral blood

DFT investigation of iron-doped boron nitride nanoparticles for anastrozole drug delivery and molecular interaction

Development of ALL-Hematotox: predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia

Abstract Immune effector cell–associated hematotoxicity (ICAHT) is a major B-cell targeted chimeric antigen receptor (CAR) T-cell related toxicity. Although ICAHT incidence and severity is documented in large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and multiple myeloma (MM), ICAHT has not been described in B-cell acute lymphoblastic leukemia (B-ALL). Similarly, the CAR-HEMATOTOX (CAR-HT) model, designed to predict severe prolonged neutropenia (≥14 days of absolute neutrophil count [ANC] <500/μL), has been validated in LBCL, MCL, and MM, but not in B-ALL. As B-ALL bone marrow (BM) infiltration can impact cytopenias, we sought to describe ICAHT and assess CAR-HT for predicting hematotoxicity in B-ALL. In a cohort of 156 children and young adults with relapsed/refractory B-ALL, the median duration of severe neutropenia (ANC <500/μL) was 13 days (95% confidence interval, 10-16 days), with 83 (53%) experiencing grade ≥3 ICAHT. Applying CAR-HT, nearly 90% were classified as high risk, demonstrating limited discriminative power and prompting further development. Using the association identified between BM disease burden and postinfusion neutropenia (r = 0.64, P < .0001), we developed the ALL-Hematotox (ALL-HT) score, which substitutes BM disease burden for ferritin in CAR-HT. The ALL-HT score associated with severe prolonged neutropenia (area under the curve = 0.84, P < .0001), and appropriately discriminated high-risk patients (47%) who had more cumulative days of neutropenia (26 vs 4 days; P < .0001), fewer rates of complete response (88% vs 98%; P = .03), and shorter median overall survival (9.8 vs 24 months; log-rank P = .0002). ALL-HT was also validated in 2 independent cohorts. The ALL-HT score refines a widely accepted predictive model of postinfusion hematotoxicity, which is applicable in B-ALL.

Why is InO’s divine veil not protective against resistance?

Honing CAR T cells to tackle acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in R/R AML. Redirecting the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123, or CLEC12A has occasionally yielded morphologic leukemia-free states but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations are largely due to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multiantigen targeting, logic gating, and emerging cell engineering solutions offer new possibilities to better direct T-cell specificity and sensitivity toward AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T-cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges, and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.

Trump’s nominee for NIH chief talks frozen grants and fostering ‘scientific dissent’

Targeting senescent stemlike subpopulations in Philadelphia chromosome–like acute lymphoblastic leukemia

Abstract Philadelphia chromosome–like B-cell acute lymphoblastic leukemia (Ph-like ALL) is driven by genetic alterations that induce constitutive kinase signaling and is associated with chemoresistance and high relapse risk in children and adults. Preclinical studies in the most common CRLF2-rearranged/JAK pathway-activated Ph-like ALL subtype have revealed variable responses to JAK inhibitor-based therapies, suggesting incomplete oncogene addiction and highlighting a need to elucidate alternative biologic dependencies and therapeutic vulnerabilities, whereas the ABL-class Ph-like ALL subtype seems preferentially sensitive to SRC/ABL- or PDGFRB-targeting inhibitors. Which patients may be responsive vs resistant to tyrosine kinase inhibitor (TKI)–based precision medicine approaches remains a critical knowledge gap. Using bulk and single-cell multiomics analyses, we profiled residual cells from CRLF2-rearranged or ABL1-rearranged Ph-like ALL patient–derived xenograft models treated in vivo with targeted inhibitors to identify TKI-resistant subpopulations and potential mechanisms of therapeutic escape. We detected a specific MYC dependency in Ph-like ALL cells and defined a new leukemia cell subpopulation with senescence-associated stem cell-like features regulated by AP-1 transcription factors. This dormant ALL subpopulation was effectively eradicated by dual pharmacologic inhibition of BCL-2 and JAK/STAT or SRC/ABL pathways, a clinically relevant therapeutic strategy. Single cell–derived molecular signatures of this senescence and stem/progenitor-like subpopulation further predicted poor clinical outcomes associated with other high-risk genetic subtypes of childhood B-ALL and thus may have broader prognostic applicability beyond Ph-like ALL.

Ancient puppets that smile or scowl hint at shared rituals

Single-cell epigenetic and clonal analysis decodes disease progression in pediatric acute myeloid leukemia

Abstract Pediatric acute myeloid leukemia (pAML) is a clonal disease with recurrent genetic alterations that affect epigenetic states. However, the implications of epigenetic dysregulation in disease progression remain unclear. Here, we interrogated single-cell and clonal level chromatin accessibility of bone marrow samples from 28 patients with pAML representing multiple subtypes using mitochondrial single-cell assay for transposase-accessible chromatin with sequencing, which revealed distinct differentiation hierarchies and abnormal chromatin accessibility in a subtype-specific manner. Innate immune signaling was commonly enhanced across subtypes and related to improved advantage of clonal competition and unfavorable prognosis, with further reinforcement in a relapse-associated leukemia stem cell–like population. We identified a panel of 31 innate immunity–related genes to improve the risk classification of patients with pAML. By comparing paired diagnosis and postchemotherapy relapse samples, we showed that primitive cells significantly reduced major histocompatibility complex class II signaling, suggesting an immune evasion mechanism to facilitate their expansion at relapse. Key regulators orchestrating cell cycle dysregulation were identified to contribute to pAML relapse in drug-resistant clones. Our work establishes the single-cell chromatin accessibility landscape at clonal resolution and reveals the critical involvement of epigenetic disruption, offering insights into classification and targeted therapies of patients with pAML.

Make hematopoiesis great again: countering oxidative stress!

Azacitidine and venetoclax for HR-MDS: election results pending

DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia

Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.