bims-tremyl 2024-03-31 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2024–03–31
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial.
Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.
Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML).
Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.
Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent.
The presence of additional cytogenetic abnormalities (ACAs) or Philadelphia chromosome variants do not adversely affect the achievement of treatment-free remission in chronic myeloid leukemia.
Double-negative T cells utilize a TNFα-JAK1-ICAM-1 cytotoxic axis against acute myeloid leukemia.
Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes.
Proteomics for optimizing therapy in acute myeloid leukemia: venetoclax plus hypomethylating agents versus conventional chemotherapy.
Solid organ transplant recipients exhibit more TET2-mutant clonal hematopoiesis of indeterminate potential not driven by increased transplantation risk.
Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.
Natural history of clonal haematopoiesis seen in real-world haematology settings.
DISRUPTION OF POLYUNSATURATED FATTY ACID BIOSYNTHESIS DRIVES STING-DEPENDENT ACUTE MYELOID LEUKEMIA CELL MATURATION AND DEATH.
XPO1 inhibition displays anti-leukemia efficacy against DNMT3A-mutant acute myeloid leukemia via downregulating glutathione pathway.
Enhanced MAPK signaling induced by CSF3Rmutants confers dependence to DUSP1 for leukemic transformation.
Immunophenotypic characterisation of acute myeloid leukaemia with UBTF tandem duplications.
Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial.
Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.
Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.
Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study.
Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?
Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity.
Measurable Residual Disease Detection in Acute Myeloid Leukemia: Current Challenges and Future Directions.
Acute myeloid leukemia with mast cell differentiation is characterized by interstitial mast cells, complex karyotype, TP53 alterations and poor prognosis.
BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.
Identification of novel NUP98 fusion partners and co-mutations in Acute Myeloid Leukemia: an adult cohort study.
ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?
AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.
Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia.
The critical role of the bone marrow stromal microenvironment for development of drug screening platforms in leukemia.
Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation: Significance of Novel Transplantation Techniques.
Larger or longer grants unlikely to push senior scientists towards high-risk, high-reward work.
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
Embracing cancer complexity: Hallmarks of systemic disease.
Generating human bone marrow organoids for disease modeling and drug discovery.
Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.

Lancet Haematol. 2024 Apr;pii: S2352-3026(24)00034-6. [Epub ahead of print]11(4): e287-e298

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial.

Alexandre Bazinet, Hagop Kantarjian, Alex Bataller, Naveen Pemmaraju, Gautam Borthakur, Kelly Chien, Yesid Alvarado, Prithviraj Bose, Elias Jabbour, Musa Yilmaz, Courtney DiNardo, Ghayas Issa, Guillermo Montalban-Bravo, Nicholas Short, Koji Sasaki, Debra Bull-Linderman, Naval Daver, Guillermo Garcia-Manero, Farhad Ravandi, Tapan Kadia.

BACKGROUND: Patients with acute myeloid leukaemia have high rates of relapse, especially if they are unable to complete standard consolidation strategies or allogeneic haematopoietic stem-cell transplantation (HSCT). The phase 3 QUAZAR AML-001 study showed an overall survival benefit with oral azacitidine maintenance. The BCL2 inhibitor venetoclax is highly active in acute myeloid leukaemia and synergistic with azacitidine. We aimed to evaluate the efficacy and safety of low dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia.
METHODS: We performed a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center in the USA. Eligible patients were adults (aged ≥18 years) with a WHO 2016 diagnosis of acute myeloid leukaemia in complete remission or complete remission with incomplete blood count recovery following intensive or low-intensity induction and not immediately eligible for HSCT. Eastern Cooperative Oncology Group performance status had to be 3 or less. Patients were assigned to maintenance therapy with azacitidine 50 mg/m2 intravenously or subcutaneously for 5 days and venetoclax 400 mg orally for 7 days or 14 days. The primary outcome was relapse-free survival. The study was closed early due to slow accrual. All patients were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04062266).
FINDINGS: Between Sept 26, 2019, and Oct 26, 2022, 35 patients were enrolled, of whom 25 (71%) were assigned to cohort 1 following intensive induction and ten (29%) to cohort 2 following low-intensity induction. Of 35 patients, 18 (51%) were male and 17 (49%) were female. The median age was 55 years (IQR 41-62). The median number of cycles given was 9 (IQR 2-22) and median follow-up time was 23·3 months (IQR 9·0-30·0). The median relapse-free survival was not reached (95% CI 20·2 to not calculable) in the full cohort, not reached (29·1 to not calculable) in cohort 1, and 30·3 months (16·5 to not calculable) in cohort 2. The 2-year relapse-free survival was 65% (95% CI 50-85) in the full cohort, 71% (53-94) in cohort 1, and 52% (27-100) in cohort 2. The most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=6), lung infection (n=4), leukopenia (n=4), and neutropenia (n=3). No deaths occurred during maintenance therapy.
INTERPRETATION: Low dose azacitidine plus venetoclax is a feasible maintenance strategy in acute myeloid leukaemia following intensive and low-intensity induction.
FUNDING: University of Texas MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech.

DOI: https://doi.org/10.1016/S2352-3026(24)00034-6
Leukemia. 2024 Mar 27.

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.

Shai Shimony, Jacqueline S Garcia, Julia Keating, Evan C Chen, Marlise R Luskin, Maximilian Stahl, Donna S Neuberg, Daniel J DeAngelo, Richard M Stone, R Coleman Lindsley.

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

DOI: https://doi.org/10.1038/s41375-024-02230-w
Leuk Lymphoma. 2024 Mar 27. 1-8

Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML).

Jorge Cortes, Brian A Jonas, Gary Schiller, Alice Mims, Gail J Roboz, Andrew H Wei, Pau Montesinos, P Brent Ferrell, Karen Wl Yee, Pierre Fenaux, Anthony Schwarer, Justin M Watts.

  Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

Keywords:  IDH1 mutation; Olutasidenib; acute myeloid leukemia

DOI:  https://doi.org/10.1080/10428194.2024.2333451
Leukemia. 2024 Mar 28.

Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.

Annamaria Brioli, Elza Lomaia, Christian Fabisch, Tomasz Sacha, Hana Klamova, Elena Morozova, Aleksandra Golos, Philipp Ernst, Ulla Olsson-Stromberg, Daniela Zackova, Franck E Nicolini, Han Bao, Fausto Castagnetti, Elzbieta Patkowska, Jiri Mayer, Klaus Hirschbühl, Helena Podgornik, Edyta Paczkowska, Anne Parry, Thomas Ernst, Astghik Voskanyan, Elzbieta Szczepanek, Susanne Saussele, Georg-Nikolaus Franke, Alexander Kiani, Edgar Faber, Stefan Krause, Luis Felipe Casado, Krzysztof Lewandowski, Matthias Eder, Peter Anhut, Justyna Gil, Thomas Südhoff, Holger Hebart, Sonja Heibl, Markus Pfirrmann, Andreas Hochhaus, Michael Lauseker.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

DOI: https://doi.org/10.1038/s41375-024-02204-y
Haematologica. 2024 Mar 28.

Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent.

Nickolas Steinauer, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek A Mangaonkar, Antoine N Saliba, Mehrdad Torghabeh, Mark R Litzow, William J Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Cecilia Arana Yi, Ayalew Tefferi, Naseema Gangat.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.284962
Am J Hematol. 2024 Mar 28.

The presence of additional cytogenetic abnormalities (ACAs) or Philadelphia chromosome variants do not adversely affect the achievement of treatment-free remission in chronic myeloid leukemia.

Fadi G Haddad, Koji Sasaki, Ghayas C Issa, Elias Jabbour, Hagop Kantarjian.

DOI: https://doi.org/10.1002/ajh.27307
Blood Adv. 2024 Mar 28. pii: bloodadvances.2023011739. [Epub ahead of print]

Double-negative T cells utilize a TNFα-JAK1-ICAM-1 cytotoxic axis against acute myeloid leukemia.

Enoch Tin, JongBok Lee, Ismat Khatri, Yoosu Na, Mark D Minden, Li Zhang.

Allogeneic double-negative T cells (DNTs) are a rare T cell subset that effectively target acute myeloid leukemia (AML) without inducing graft-vs-host disease in an allogeneic setting. A phase I clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy among patients with relapsed AML. However, the molecular mechanisms of DNT-mediated cytotoxicity against AML remain elusive. Thus, we utilized a flow cytometry-based high throughput screening to compare the surface molecule expression profile on DNTs during their interaction with DNT-susceptible or -resistant AML cells and identified a TNFα-dependent cytotoxic pathway in DNT-AML interaction. TNFα secreted by DNTs, upon encountering susceptible AML targets, sensitized AML cells to DNT-mediated killing, including those otherwise resistant to DNTs. Mechanistically, TNFα upregulated ICAM-1 on AML cells through a noncanonical JAK1-dependent pathway. DNTs then engaged with AML cells more effectively through an ICAM-1 receptor, LFA-1, leading to enhanced killing. These results reveal a TNFα-JAK1-ICAM-1 axis in DNT-mediated cytotoxicity against AML to improve therapeutic efficacy.

DOI: https://doi.org/10.1182/bloodadvances.2023011739
Blood Adv. 2024 Mar 25. pii: bloodadvances.2023011512. [Epub ahead of print]

Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes.

Chi-Yuan Yao, Chien-Chin Lin, Yu-Hung Wang, Chein-Jun Kao, Xavier Cheng-Hong Tsai, Hsin-An Hou, Hwei-Fang Tien, Chia-Lang Hsu, Wen-Chien Chou.

The human kinome, which comprises over five hundred kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndrome (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified seven kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the KInase Stratification Score (KISS) by combining the weighted expressions of the seven kinases, and validated its prognostic significance in two external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for genesets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer (GDSC) database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

DOI: https://doi.org/10.1182/bloodadvances.2023011512
Leukemia. 2024 Mar 26.

Proteomics for optimizing therapy in acute myeloid leukemia: venetoclax plus hypomethylating agents versus conventional chemotherapy.

Eduardo Sabino de Camargo Magalhães, Stefan Edward Hubner, Brandon Douglas Brown, Yihua Qiu, Steven Mitchell Kornblau.

The use of Hypomethylating agents combined with Venetoclax (VH) for the treatment of Acute Myeloid Leukemia (AML) has greatly improved outcomes in recent years. However not all patients benefit from the VH regimen and a way to rationally select between VH and Conventional Chemotherapy (CC) for individual AML patients is needed. Here, we developed a proteomic-based triaging strategy using Reverse-phase Protein Arrays (RPPA) to optimize therapy selection. We evaluated the expression of 411 proteins in 810 newly diagnosed adult AML patients, identifying 109 prognostic proteins, that divided into five patient expression profiles, which are useful for optimizing therapy selection. Furthermore, using machine learning algorithms, we determined a set of 14 proteins, among those 109, that were able to accurately recommend therapy, making it feasible for clinical application. Next, we identified a group of patients who did not benefit from either VH or CC and proposed target-based approaches to improve outcomes. Finally, we calculated that the clinical use of our proteomic strategy would have led to a change in therapy for 30% of patients, resulting in a 43% improvement in OS, resulting in around 2600 more cures from AML per year in the United States.

DOI: https://doi.org/10.1038/s41375-024-02208-8
Clin Cancer Res. 2024 Mar 29.

Solid organ transplant recipients exhibit more TET2-mutant clonal hematopoiesis of indeterminate potential not driven by increased transplantation risk.

Alexander J Silver, Caitlyn Vlasschaert, Taralynn Mack, Brian Sharber, Yaomin Xu, Alexander G Bick, C Wright Pinson, Michael R Savona.

PURPOSE: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants.
EXPERIMENTAL DESIGN: We use two national biobank cohorts comprised of >650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts.
RESULTS: We find individuals with an allograft prior to their biobank enrollment had an increased prevalence of TET2 mutations (OR 1.90; p = 4.0e-4), but individuals who received transplants post-enrollment had a CHIP mutation spectrum similar to that of the general population, without enrichment of TET2. Additionally, we do not observe an association between CHIP and risk of incident transplantation among the overall population (HR 1.02; p = 0.91). And in an exploratory analysis, we do not find evidence for a strong association between CHIP and rates of transplant complications such as rejection or graft failure.
CONCLUSIONS: These results demonstrate that recipients of solid organ transplants display a unique pattern of clonal hematopoiesis with enrichment of TET2 driver mutations, the causes of which remain unclear and are deserving of further study.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-3840
Clin Lymphoma Myeloma Leuk. 2024 Mar 11. pii: S2152-2650(24)00108-3. [Epub ahead of print]

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.

Luis E Aguirre, Akriti Jain, Somedeb Ball, Najla Al Ali, Virginia O Volpe, Sara Tinsley-Vance, David Sallman, Kendra Sweet, Jeffrey Lancet, Eric Padron, Seongseok Yun, Andrew Kuykendall, Rami Komrokji.

   BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation.
PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations.
RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib.
CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

Keywords:  Clonal architecture; JAK; MPN; NGS; Prognosis

DOI:  https://doi.org/10.1016/j.clml.2024.03.001
Br J Haematol. 2024 Mar 24.

Natural history of clonal haematopoiesis seen in real-world haematology settings.

Shyam A Patel, William K Gerber, Rena Zheng, Shrinkhala Khanna, Lloyd Hutchinson, Gregory A Abel, Jan Cerny, Brandon A DaSilva, Tian Y Zhang, Muthalagu Ramanathan, Salwa Khedr, William Selove, Bruce Woda, Patricia M Miron, Anne W Higgins, Jonathan M Gerber.

  Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

Keywords:  CHIP; acute myeloid leukaemia; clonal haematopoiesis; epigenetics; myelodysplastic syndrome; myeloid genomics

DOI:  https://doi.org/10.1111/bjh.19423
J Biol Chem. 2024 Mar 22. pii: S0021-9258(24)01709-5. [Epub ahead of print] 107214

DISRUPTION OF POLYUNSATURATED FATTY ACID BIOSYNTHESIS DRIVES STING-DEPENDENT ACUTE MYELOID LEUKEMIA CELL MATURATION AND DEATH.

Joice Kanefsky, Mary Basse, Judith Sokei, Orsola di Martino, Liana Valin, Yorrick Jaspers, Esteban Martinez, Jacklyn Huhn, Daniela Di Marcantonio, Jeffrey A Magee, Aaron R Goldman, Hsin-Yao Tang, Francesca Ferraro, Stephan Kemp, David L Wiest, Stephen M Sykes.

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that Fatty Acid Desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to health controls, and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling including depletion of PUFAs from the phospholipids, phosphatidylserine and phosphatidylethanolamine. These lipidomic alterations were accompanied by an induction of inflammatory and STING-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML (PD-AML) cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated PD-AML survival, however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.

DOI: https://doi.org/10.1016/j.jbc.2024.107214
Ann Hematol. 2024 Mar 23.

XPO1 inhibition displays anti-leukemia efficacy against DNMT3A-mutant acute myeloid leukemia via downregulating glutathione pathway.

Xiaoya Cai, Ying Liu, Huimin Li, Yimei Que, Min Xiao, Ying Wang, Xiong Wang, Dengju Li.

  Acute myeloid leukemia (AML) patients with DNA methyltransferase 3A (DNMT3A) mutation display poor prognosis, and targeted therapy is not available currently. Our previous study identified increased expression of Exportin1 (XPO1) in DNMT3AR882H AML patients. Therefore, we further investigated the therapeutic effect of XPO1 inhibition on DNMT3AR882H AML. Three types of DNMT3AR882H AML cell lines were generated, and XPO1 was significantly upregulated in all DNMT3AR882H cells compared with the wild-type (WT) cells. The XPO1 inhibitor selinexor displayed higher potential in the inhibition of proliferation, promotion of apoptosis, and blockage of the cell cycle in DNMT3AR882H cells than WT cells. Selinexor also significantly inhibited the proliferation of subcutaneous tumors in DNMT3AR882H AML model mice. Primary cells with DNMT3A mutations were more sensitive to selinexor in chemotherapy-naive AML patients. RNA sequencing of selinexor treated AML cells revealed that the majority of metabolic pathways were downregulated after selinexor treatment, with the most significant change in the glutathione metabolic pathway. Glutathione inhibitor L-Buthionine-(S, R)-sulfoximine (BSO) significantly enhanced the apoptosis-inducing effect of selinexor in DNMT3AWT/DNMT3AR882H AML cells. In conclusion, our work reveals that selinexor displays anti-leukemia efficacy against DNMT3AR882H AML via downregulating glutathione pathway. Combination of selinexor and BSO provides novel therapeutic strategy for AML treatment.

Keywords:  Acute myeloid leukaemia; DNA methyltransferase 3A; exportin-1; glutathione

DOI:  https://doi.org/10.1007/s00277-024-05706-y
Blood Adv. 2024 Mar 26. pii: bloodadvances.2023010830. [Epub ahead of print]

Enhanced MAPK signaling induced by CSF3Rmutants confers dependence to DUSP1 for leukemic transformation.

Meenu Kesarwani, Zachary Kincaid, Mohammad Azhar, Mohammad Azam.

Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). While inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a pro-apoptotic response. Consequently, malignancies reliant on elevated MAPK signaling employ MAPK-feedback regulators to intricately modulate the signaling output, prioritizing proliferation and survival while dampening the apoptotic stimuli. Herein, we demonstrate that enhanced MAPK signaling in CSF3R (Granulocyte-colony stimulating factor receptor)-driven leukemia upregulates the expression of Dual specificity phosphatase 1 (DUSP1) to suppress the apoptotic stimuli crucial for leukemogenesis. Consequently, genetic deletion of Dusp1 in mice conferred synthetic lethality to CSF3R-induced leukemia. Mechanistically, DUSP1 depletion in leukemic context causes activation of JNK1/2 that results in induced expression of BIM and P53 while suppressing the expression BCL2 that selectively triggers apoptotic response in leukemic cells. Pharmacological inhibition of DUSP1 by BCI (a DUSP1 inhibitor) alone lacked anti-leukemic activity due to ERK1/2 rebound caused by off-target inhibition of DUSP6. Consequently, a combination of BCI with a MEK inhibitor successfully cured CSF3R-induced leukemia in a preclinical mouse model. Our findings underscore the pivotal role of DUSP1 in leukemic transformation driven by enhanced MAPK signaling and advocate for the development of a selective DUSP1 inhibitor for curative treatment outcomes.

DOI: https://doi.org/10.1182/bloodadvances.2023010830
Br J Haematol. 2024 Mar 28.

Immunophenotypic characterisation of acute myeloid leukaemia with UBTF tandem duplications.

Sean Harrop, Phillip C Nguyen, Samuel Robinson, Tamia Nguyen, Ing Soo Tiong, Neil Came, Kylie Baldwin, Vuong Nguyen, Kah Lok Chan, Piers Blombery, David Westerman.

DOI: https://doi.org/10.1111/bjh.19427
Blood Cancer J. 2024 Mar 27. 14(1): 56

Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial.

Niek G van der Maas, Jurjen Versluis, Kazem Nasserinejad, Joost van Rosmalen, Thomas Pabst, Johan Maertens, Dimitri Breems, Markus Manz, Jacqueline Cloos, Gert J Ossenkoppele, Yngvar Floisand, Patrycja Gradowska, Bob Löwenberg, Gerwin Huls, Douwe Postmus, Francesco Pignatti, Jan J Cornelissen.

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a "7 + 3" induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81-1.69), 1.05 (95% CI 0.86-1.30), 1.00 (95% CI 0.84-1.19), and 1.02 (95% CI 0.87-1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

DOI: https://doi.org/10.1038/s41408-024-01037-3
Nature. 2024 Mar 27.

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Sandi Radko-Juettner, Hong Yue, Jacquelyn A Myers, Raymond D Carter, Alexis N Robertson, Priya Mittal, Zhexin Zhu, Baranda S Hansen, Katherine A Donovan, Moritz Hunkeler, Wojciech Rosikiewicz, Zhiping Wu, Meghan G McReynolds, Shourya S Roy Burman, Anna M Schmoker, Nada Mageed, Scott A Brown, Robert J Mobley, Janet F Partridge, Elizabeth A Stewart, Shondra M Pruett-Miller, Behnam Nabet, Junmin Peng, Nathanael S Gray, Eric S Fischer, Charles W M Roberts.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

DOI: https://doi.org/10.1038/s41586-024-07250-1
Mol Cell. 2024 Mar 22. pii: S1097-2765(24)00175-8. [Epub ahead of print]

Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.

Prajwal C Boddu, Abhishek K Gupta, Rahul Roy, Bárbara De La Peña Avalos, Anne Olazabal-Herrero, Nils Neuenkirchen, Joshua T Zimmer, Namrata S Chandhok, Darren King, Yasuhito Nannya, Seishi Ogawa, Haifan Lin, Matthew D Simon, Eloise Dray, Gary M Kupfer, Amit Verma, Karla M Neugebauer, Manoj M Pillai.

  Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

Keywords:  DNA damage response; R-loops; RNA polymerase II; SF3B1; Sin3/HDAC; U2AF1; WDR5; co-transcriptional splicing; spliceosome; transcription

DOI:  https://doi.org/10.1016/j.molcel.2024.02.032
BMJ Open. 2024 Mar 29. 14(3): e076321

Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study.

Colombe Saillard, Sarah Cuvelier, Charlène Villaron-Goetgheluck, Jean-Marie Boher, Leonor Almeida-Lopez, Anne-Gaelle Le Corroller, Pauline Denis, Céline Rivieccio, Sarah Calvin, Norbert Vey, Cécile Bannier-Braticevic.

   OBJECTIVES: Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general deterioration of the patient's health and quality of life. Furthermore, allo-HSCT can be responsible for significant toxicity with risks of graft-versus-host disease (GvHD). Developing strategies to prevent physical deconditioning, undernutrition and psychological distress could help maintain a satisfactory general state of health before transplantation and thus limit these deleterious effects. This protocol evaluates the feasibility and adherence to a personalised prehabilitation programme, which can be modulated and assisted by connected objects, provided from the diagnosis to the allo-HSCT.
METHODS AND ANALYSIS: This multicentre interventional study will include 50 patients treated for AML or high-risk MDS with intensive chemotherapy and eligible for allo-HSCT. The intervention consists of a coached, supervised or self-directed physical activity programme, organised during the hospitalisation phases and periods at home. At the same time, patients will receive a weekly dietary follow-up. The whole intervention is controlled and modulated through the use of a dedicated application and connected objects allowing adaptation and individualisation. The rate of participation in the prescribed physical activity sessions will assess the feasibility of this study. In addition, the evolution of physical capacities (Short Physical Performance Battery, grip and quadriceps strengths), psychosocial parameters (Functional Assessment of Cancer Therapy - Leukaemia, Functional Assessment of Cancer Therapy - Fatigue, subjective well-being, Hospital Anxiety and Depression Scale, self-efficacy, Coach-Athlete Relationship Questionnaire, interviews) and clinical status (weight, lean body mass, survival rate, number of infections, days of hospitalisation, GvHD) will be evaluated.
ETHICS AND DISSEMINATION: The study procedures have been approved by the National Ethics Committee (21.00223.000003). Consent is given in person by each participant. The information collected on the participants contains only a non-identifiable study identifier. The results of this protocol will be published in a scientific paper and communicated to the medical staff of the medical centre.
TRIAL REGISTRATION NUMBER: NCT03595787.

Keywords:  Adult oncology; HAEMATOLOGY; Nutritional support; Quality of Life; SPORTS MEDICINE

DOI:  https://doi.org/10.1136/bmjopen-2023-076321
Leukemia. 2024 Mar 26.

Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?

Hagop Kantarjian, Susan Branford, Massimo Breccia, Jorge Cortes, Fadi G Haddad, Andreas Hochhaus, Timothy Hughes, Ghayas C Issa, Elias Jabbour, Franck E Nicolini, Koji Sasaki, Francois Xavier-Mahon.

DOI: https://doi.org/10.1038/s41375-024-02229-3
Nature. 2024 Mar 27.

Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity.

Jason B Ross, Lara M Myers, Joseph J Noh, Madison M Collins, Aaron B Carmody, Ronald J Messer, Erica Dhuey, Kim J Hasenkrug, Irving L Weissman.

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.

DOI: https://doi.org/10.1038/s41586-024-07238-x
Biomedicines. 2024 Mar 07. pii: 599. [Epub ahead of print]12(3):

Measurable Residual Disease Detection in Acute Myeloid Leukemia: Current Challenges and Future Directions.

Jennifer Moritz, Antonia Schwab, Andreas Reinisch, Armin Zebisch, Heinz Sill, Albert Wölfler.

  Acute myeloid leukemia (AML) is an aggressive malignant disease with a high relapse rate due to the persistence of chemoresistant cells. To some extent, these residual cells can be traced by sensitive flow cytometry and molecular methods resulting in the establishment of measurable residual disease (MRD). The detection of MRD after therapy represents a significant prognostic factor for predicting patients' individual risk of relapse. However, due to the heterogeneity of the disease, a single sensitive method for MRD detection applicable to all AML patients is lacking. This review will highlight the advantages and limitations of the currently available detection methods-PCR, multiparameter flow cytometry, and next generation sequencing-and will discuss emerging clinical implications of MRD test results in tailoring treatment of AML patients.

Keywords:  MRD detection methods; acute myeloid leukemia; measurable residual disease; postremission decision; risk-stratification

DOI:  https://doi.org/10.3390/biomedicines12030599
Haematologica. 2024 Mar 28.

Acute myeloid leukemia with mast cell differentiation is characterized by interstitial mast cells, complex karyotype, TP53 alterations and poor prognosis.

Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.284976
Cancer Discov. 2024 Mar 28.

BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.

Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, M James You, Helen Piwnica-Worms, Boyi Gan.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1220
Blood Adv. 2024 Mar 27. pii: bloodadvances.2023012479. [Epub ahead of print]

Identification of novel NUP98 fusion partners and co-mutations in Acute Myeloid Leukemia: an adult cohort study.

James S Heald, Aleix Méndez López, Miguel L Pato, Neus Ruiz-Xiville, Marta Cabezón, Lurdes Zamora, Susana Vives, Rosa Coll Jorda, Clara Maluquer Artigal, Isabel Granada, Francesc Sole, Manel Esteller, María Berdasco.

DOI: https://doi.org/10.1182/bloodadvances.2023012479
Leukemia. 2024 Mar 27.

ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?

Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Nicolaus Kröger, Matthias Stelljes, Tobias Gedde-Dahl, Igor Wolfgang Blau, Thomas Schroeder, Urpu Salmenniemi, Alexander Kulagin, Régis Peffault de Latour, Stephan Mielke, Robert Zeiser, Ivan Moiseev, Hélène Schoemans, Christian Koenecke, Zinaida Peric.

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75-0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.

DOI: https://doi.org/10.1038/s41375-024-02225-7
Cell Death Differ. 2024 Mar 27.

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

Jia Jia, Wenbo Ji, Antoine N Saliba, Clifford M Csizmar, Kaiqin Ye, Lei Hu, Kevin L Peterson, Paula A Schneider, X Wei Meng, Annapoorna Venkatachalam, Mrinal M Patnaik, Jonathan A Webster, B Douglas Smith, Gabriel Ghiaur, Xinyan Wu, Jun Zhong, Akhilesh Pandey, Karen S Flatten, Qingmei Deng, Hongzhi Wang, Scott H Kaufmann, Haiming Dai.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

DOI: https://doi.org/10.1038/s41418-024-01283-9
Cell Death Discov. 2024 Mar 28. 10(1): 157

Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia.

Caroline Spertini, Alexandre P Bénéchet, Flora Birch, Axel Bellotti, Mónica Román-Trufero, Caroline Arber, Holger W Auner, Robert A Mitchell, Olivier Spertini, Tatiana Smirnova.

The malignant microenvironment plays a major role in the development of resistance to therapies and the occurrence of relapses in acute myeloid leukemia (AML). We previously showed that interactions of AML blasts with bone marrow macrophages (MΦ) shift their polarization towards a protumoral (M2-like) phenotype, promoting drug resistance; we demonstrated that inhibiting the colony-stimulating factor-1 receptor (CSF1R) repolarizes MΦ towards an antitumoral (M1-like) phenotype and that other factors may be involved. We investigated here macrophage migration inhibitory factor (MIF) as a target in AML blast survival and protumoral interactions with MΦ. We show that pharmacologically inhibiting MIF secreted by AML blasts results in their apoptosis. However, this effect is abrogated when blasts are co-cultured in close contact with M2-like MΦ. We next demonstrate that pharmacological inhibition of MIF secreted by MΦ, in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), efficiently reprograms MΦ to an M1-like phenotype that triggers apoptosis of interacting blasts. Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.

DOI: https://doi.org/10.1038/s41420-024-01924-5
Exp Hematol. 2024 Mar 27. pii: S0301-472X(24)00071-7. [Epub ahead of print] 104212

The critical role of the bone marrow stromal microenvironment for development of drug screening platforms in leukemia.

Rhiannon G Panting, Rishi S Kotecha, Laurence C Cheung.

  Extensive research over the past 50 years has resulted in significant improvements in survival for patients diagnosed with leukemia. Despite this, a subgroup of patients harboring high-risk genetic alterations still suffer from poor outcomes. There is a desperate need for new treatments to improve survival, yet consistent failure exists in translation of in vitro drug development to clinical application. Preclinical screening conventionally utilizes tumor cell monocultures to assess drug activity, however emerging research has acknowledged the vital role of the tumor microenvironment in treatment resistance and disease relapse. Current co-culture drug screening methods frequently employ fibroblasts as the designated stromal cell component. Alternative stromal cell types that are known to contribute to chemoresistance are often absent in preclinical evaluation of drug efficacy. This review highlights mechanisms of chemoresistance by a range of different stromal constituents present in the bone marrow microenvironment. Utilizing an array of stromal cell types at early stages of drug screening may enhance the translation of in vitro drug development to clinical use. Ultimately, we highlight the need to consider the bone marrow microenvironment in drug screening platforms for leukemia, in order to develop superior therapies for the treatment of high-risk patients with poor prognostic outcomes.

Keywords:  bone marrow microenvironment; chemoresistance; drug screening; leukemia; stroma

DOI:  https://doi.org/10.1016/j.exphem.2024.104212
Blood Adv. 2024 Mar 27. pii: bloodadvances.2023012175. [Epub ahead of print]

Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation: Significance of Novel Transplantation Techniques.

Alicja Sadowska-Klasa, Sezen Özkök, Hu Xie, Wendy M Leisenring, Danniel Zamora, Sachiko Seo, Jordan Sheldon, Stephanie J Lee, Keith R Jerome, Margaret L Green, Michael J Boeckh.

Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 187 episodes of late CMV disease among 2469 day 100 survivors and the estimated cumulative incidence of first late CMV disease was 6.7% (95% CI 5.6-%-7.6%) with no difference between the PET 6.7% (95% CI 5.7%-7.8%) and the letermovir group 5.4% (95% CI 3.2%-8.3%). 32 (1.3%) patients had a second episode of late CMV disease. In multivariable Cox regression models, post-transplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia detected before day 100, corticosteroid treatment after day 100 at dose ≥1mg/kg, acute and chronic GvHD, lymphopenia, HLA mismatched related donors status and recipient age were also associated with late CMV disease. HLA mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by year two after HCT. In summary, late CMV disease continues to occur in the current era. Improved prevention strategies for late CMV disease are needed.

DOI: https://doi.org/10.1182/bloodadvances.2023012175
Nature. 2024 Mar 25.

Larger or longer grants unlikely to push senior scientists towards high-risk, high-reward work.

Dalmeet Singh Chawla.



Keywords:  Funding; Government; Institutions; Research management

DOI:  https://doi.org/10.1038/d41586-024-00929-5
Sci Adv. 2024 Mar 29. 10(13): eadm9859

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

DOI: https://doi.org/10.1126/sciadv.adm9859
Cell. 2024 Mar 28. pii: S0092-8674(24)00175-2. [Epub ahead of print]187(7): 1589-1616

Embracing cancer complexity: Hallmarks of systemic disease.

Charles Swanton, Elsa Bernard, Chris Abbosh, Fabrice André, Johan Auwerx, Allan Balmain, Dafna Bar-Sagi, René Bernards, Susan Bullman, James DeGregori, Catherine Elliott, Ayelet Erez, Gerard Evan, Mark A Febbraio, Andrés Hidalgo, Mariam Jamal-Hanjani, Johanna A Joyce, Matthew Kaiser, Katja Lamia, Jason W Locasale, Sherene Loi, Ilaria Malanchi, Miriam Merad, Kathryn Musgrave, Ketan J Patel, Sergio Quezada, Jennifer A Wargo, Ashani Weeraratna, Eileen White, Frank Winkler, John N Wood, Karen H Vousden, Douglas Hanahan.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

DOI: https://doi.org/10.1016/j.cell.2024.02.009
Nat Protoc. 2024 Mar 26.

Generating human bone marrow organoids for disease modeling and drug discovery.

Aude-Anais Olijnik, Antonio Rodriguez-Romera, Zoë C Wong, Yuqi Shen, Jasmeet S Reyat, Natalie J Jooss, Julie Rayes, Bethan Psaila, Abdullah O Khan.

The bone marrow supports and regulates hematopoiesis, responding to physiological requirements for blood cell production over ontogeny and during pathological challenges. Interactions between hematopoietic cells and niche components are challenging to study mechanistically in the human context, but are important to delineate in order to explore the pathobiology of blood and bone marrow disorders. Organoids are proving transformative in many research settings, but an accurate human bone marrow model incorporating multiple hematopoietic and stromal elements has been lacking. This protocol describes a method to generate three-dimensional, multilineage bone marrow organoids from human induced pluripotent stem cells (hiPSCs), detailing the steps for the directed differentiation of hiPSCs using a series of cytokine cocktails and hydrogel embedding. Over 18 days of differentiation, hiPSCs yield the key lineages that are present in central myelopoietic bone marrow, organized in a well-vascularized architecture that resembles native hematopoietic tissues. This presents a robust, in vitro system that can model healthy and perturbed hematopoiesis in a scalable three-dimensional microenvironment. Bone marrow organoids also support the growth of immortalized cell lines and primary cells from healthy donors and patients with myeloid and lymphoid cancers, including cell types that are poorly viable in standard culture systems. Moreover, we discuss assays for the characterization of organoids, including interrogation of pathogenic remodeling using recombinant TGF-ß treatment, and methods for organoid engraftment with exogenous cells. This protocol can be readily adapted to specific experimental requirements, can be easily implemented by users with tissue culture experience and does not require access to specialist equipment.

DOI: https://doi.org/10.1038/s41596-024-00971-7
Science. 2024 Mar 29. 383(6690): 1484-1492

Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.

Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.

Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.

DOI: https://doi.org/10.1126/science.adh2771