bims-tremyl 2023-05-28 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023–05–28
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML.
UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome.
A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies.
A venetoclax and azacitidine bridge-to-transplant strategy for NPM1-mutated acute myeloid leukaemia in molecular failure.
Reprogramming of Acute Myeloid Leukemia Patients Cells: Harboring Cancer Mutations Requires Targeting of AML Hierarchy.
Clinical roles of TIM-3 in myeloid malignancies and its importance in cellular therapy.
miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.
Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML.
First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.
Unifying targeted therapy for leukemia in the era of PARP inhibition.
Clonal Hematopoiesis in Survivors of Childhood Cancer.
Genetic separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution.
Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry.
Clonal Hematopoiesis in Myeloproliferative Neoplasms Confers a Predisposition to both Thrombosis and Cancer.
Deletion of CD36 exhibits limited impact on normal hematopoiesis and the leukemia microenvironment.
Interferon alpha-2 treatment reduces circulating neutrophil extracellular trap levels in myeloproliferative neoplasms.
Heterogeneity analysis of the CEBPAdm AML based on bZIP region mutations.
Role of the bone marrow vascular niche in chemotherapy for MLL-AF9-induced acute myeloid leukemia.
Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease.
The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.
Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: A quantitative approach.
Prevalence and clinical expression of germline predisposition to myeloid neoplasms in adults with marrow hypocellularity.
Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.
Pseudomonas aeruginosa ExoU-associated virulence in hematopoietic cell transplant and hematologic malignancy patients.
Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression.
AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.
Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.
Advances in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia.

Blood. 2023 May 22. pii: blood.2022019056. [Epub ahead of print]

Palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML.

Xuejing Shao, Aixiao Xu, Wenxin Du, Tong Xu, Yunpeng Huang, Zhimei Xia, Wei Wang, Minyi Cai, Xingya Zhang, Jianhua Zhang, Ji Cao, Xiaojun Xu, Bo Yang, Qiaojun He, Meidan Ying.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of patients who receive the most intensive treatment inevitably suffer disease relapse, likely resulting from the persistence of drug‑resistant leukemia stem cells (LSCs). AML cells especially LSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, but the mechanism involved in OXPHOS hyperactivity is unclear and a noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator of OXPHOS hyperactivity in AML cells. The depletion/inhibition of ZDHHC21 effectively induced myeloid differentiation and weakened stemness potential by inhibiting OXPHOS in AML cells. Interestingly, FLT3-ITD mutated AML cells expressed significantly higher levels of ZDHHC21 and exhibited better sensitivity to ZDHHC21 inhibition. Mechanistically, ZDHHC21 specifically catalyzed the palmitoylation of mitochondrial kinase AK2 and further activated OXPHOS in leukemic blasts. Inhibition of ZDHHC21 arrested the in vivo growth of AML cells and extended the survival of mice inoculated with AML cell lines and PDX-AML blasts. Moreover, targeting ZDHHC21 to suppress OXPHOS markedly eradicated AML blasts and enhanced chemotherapy efficacy in relapsed/refractory leukemia. Together, these findings not only uncover a new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate that ZDHHC21 inhibition is a promising therapeutic regimen for patients with AML, especially relapsed/refractory leukemia.

DOI: https://doi.org/10.1182/blood.2022019056
Blood Cancer J. 2023 May 26. 13(1): 88

UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome.

Study Alliance Leukemia (SAL)

Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52-3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02-2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08-2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.

DOI: https://doi.org/10.1038/s41408-023-00858-y
Hemasphere. 2023 Jun;7(6): e896

A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies.

Chiara Tomasoni, Alice Pievani, Benedetta Rambaldi, Andrea Biondi, Marta Serafini.

Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients.

DOI: https://doi.org/10.1097/HS9.0000000000000896
Br J Haematol. 2023 May 24.

A venetoclax and azacitidine bridge-to-transplant strategy for NPM1-mutated acute myeloid leukaemia in molecular failure.

C Sartor, L Brunetti, E Audisio, A Cignetti, L Zannoni, G Cristiano, J Nanni, R Ciruolo, F Zingarelli, E Ottaviani, A Patuelli, L Bandini, D Forte, S Sciabolacci, V Cardinali, C Papayannidis, M Cavo, M P Martelli, A Curti.

  NPM1-mutated acute myeloid leukaemia (NPM1mut AML) represents a mostly favourable/intermediate risk disease that benefits from allogeneic haematopoietic stem cell transplantation (HSCT) in case of measurable residual disease (MRD) relapse or persistence after induction chemotherapy. Although the negative prognostic role of pre-HSCT MRD is established, no recommendations are available for the management of peri-transplant molecular failure (MF). Based on the efficacy data of venetoclax (VEN)-based treatment in NPM1mut AML older patients, we retrospectively analysed the off-label combination of VEN plus azacitidine (AZA) as bridge-to-transplant strategy in 11 NPM1mut MRD-positive fit AML patients. Patients were in MRD-positive complete remission (CRMRDpos ) at the time of treatment: nine in molecular relapse and two in molecular persistence. After a median number of two cycles (range 1-4) of VEN-AZA, 9/11 (81.8%) achieved CRMRD -negative (CRMRDneg ). All 11 patients proceeded to HSCT. With a median follow-up from treatment start of 26 months, and a median post-HSCT follow-up of 19 months, 10/11 patients are alive (1 died from non-relapse mortality), and 9/10 patients are in MRDneg status. This patient series highlights the efficacy and safety of VEN-AZA to prevent overt relapse, achieve deep responses and preserve patient fitness before HSCT, in patients with NPM1mut AML in MF.

Keywords:  AML; HSCT; MRD; venetoclax

DOI:  https://doi.org/10.1111/bjh.18887
Stem Cells Transl Med. 2023 May 24. pii: szad022. [Epub ahead of print]

Reprogramming of Acute Myeloid Leukemia Patients Cells: Harboring Cancer Mutations Requires Targeting of AML Hierarchy.

Diana Golubeva, Deanna P Porras, Meaghan Doyle, Jennifer C Reid, Borko Tanasijevic, Allison L Boyd, Kinga Vojnits, Amro Elrafie, Amy Qiao, Mickie Bhatia.

  Screening of primary patient acute myeloid leukemia (AML) cells is challenging based on intrinsic characteristics of human AML disease and patient-specific conditions required to sustain AML cells in culture. This is further complicated by inter- and intra-patient heterogeneity, and "contaminating" normal cells devoid of molecular AML mutations. Derivation of induced pluripotent stem cells (iPSCs) from human somatic cells has provided approaches for the development of patient-specific models of disease biology and has recently included AML. Although reprogramming patient-derived cancer cells to pluripotency allows for aspects of disease modeling, the major limitation preventing applications and deeper insights using AML-iPSCs is the rarity of success and limited subtypes of AML disease that can be captured by reprogramming to date. Here, we tested and refined methods including de novo, xenografting, naïve versus prime states and prospective isolation for reprogramming AML cells using a total of 22 AML patient samples representing the wide variety of cytogenetic abnormalities. These efforts allowed us to derive genetically matched healthy control (isogenic) lines and capture clones found originally in patients with AML. Using fluorescently activated cell sorting, we revealed that AML reprogramming is linked to the differentiation state of diseased tissue, where use of myeloid marker CD33 compared to the stem cell marker, CD34, reduces reprogramming capture of AML+ clones. Our efforts provide a platform for further optimization of AML-iPSC generation, and a unique library of iPSC derived from patients with AML for detailed cellular and molecular study.

Keywords:  AML-induced pluripotent stem cell; acute myeloid leukemia; hematopoietic stem/progenitor cell; induced pluripotent stem cell; reprogramming; xenotransplantation

DOI:  https://doi.org/10.1093/stcltm/szad022
Blood Cell Ther. 2022 Dec 23. 5(Spec Edition): S1-S5

Clinical roles of TIM-3 in myeloid malignancies and its importance in cellular therapy.

Yoshikane Kikushige.

  Acute myeloid leukemia (AML), one of the most common hematological malignancies worldwide, is derived from a fraction of stem cells known as leukemic stem cells (LSCs), which possess self-renewal and high propagation capacities. Remaining quiescent and being resistant to conventional chemotherapy, residual LSCs after chemotherapy drive leukemia regrowth, leading to AML relapse. Therefore, the eradication of LSCs is critical for the treatment of AML. We previously identified hepatitis A virus cellular receptor 2 (HAVCR2/TIM-3) as an LSC-specific surface molecule by comparing gene expression in LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminated LSCs from HSCs within the CD34+CD38- stem cell fraction. Furthermore, AML cells secrete galectin-9, a TIM-3 ligand, in an autocrine manner, leading to constitutive TIM-3 signaling that maintains the self-renewal capacity of LSCs via the induction of β-catenin accumulation. Thus, TIM-3 is an indispensable functional molecule for human LSCs. Herein, we review the functional aspects of TIM-3 in AML and evaluate minimal/measurable residual disease with a focus on CD34+CD38-TIM-3+ LSCs. Using sequential genomic analysis of identical patients, we determined that CD34+CD38-TIM-3+ cells in the complete remission (CR) phase after allogeneic stem cell transplantation (allo-SCT) are the LSCs responsible for AML relapse. We retrospectively evaluated the incidence of TIM-3+ residual LSCs. All analyzed patients achieved CR and complete donor chimerism at the engraftment phase; however, the high frequency of residual TIM-3+ LSCs within the CD34+CD38- fraction at engraftment was a significant and independent risk factor for relapse. Residual TIM-3+ LSC levels in the engraftment phase had a stronger impact on relapse than did pre-SCT disease status. Therefore, the evaluation of residual TIM-3+ LSCs is a promising approach for predicting leukemia relapse after allo-SCT.

Keywords:  TIM-3; allo-SCT; hematopoietic stem cells; leukemic stem cells

DOI:  https://doi.org/10.31547/bct-2022-010
Front Genet. 2023 ;14 1192799

miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.

Arevik Ghazaryan, Jared A Wallace, William W Tang, Cindy Barba, Soh-Hyun Lee, Kaylyn M Bauer, Morgan C Nelson, Carissa N Kim, Chris Stubben, Warren P Voth, Dinesh S Rao, Ryan M O'Connell.

  Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.

Keywords:  OxPhos; acute myeloid leukemia; hematological malignancies; microRNA-1; prognostic biomarker

DOI:  https://doi.org/10.3389/fgene.2023.1192799
Clin Cancer Res. 2023 May 24. pii: CCR-22-3929. [Epub ahead of print]

Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML.

Christopher T Letson, Maria E Balasis, Hannah Newman, Moritz Binder, Alexis Vedder, Fumi Kinose, Markus Ball, Traci Kruer, Ariel Quintana, Terra L Lasho, Christy M Finke, Luciana L Almada, Jennifer M Grants, Guolin Zhang, Martin E Fernandez-Zapico, Alexandre Gaspar-Maia, Jeffrey Lancet, Rami Komrokji, Eric Haura, David A Sallman, Gary W Reuther, Aly Karsan, Uwe Rix, Mrinal M Patnaik, Eric Padron.

BACKGROUND: Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi.
EXPERIMENTAL DESIGN: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and PDX models of disease. We utilized standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models.
RESULTS: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy.
CONCLUSION: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3929
Leuk Res. 2023 May 09. pii: S0145-2126(23)00573-8. [Epub ahead of print]130 107308

First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.

Marie Balsat, Vincent Alcazer, Gabriel Etienne, Françoise Huguet, Marc Berger, Emilie Cayssials, Aude Charbonnier, Martine Escoffre-Barbe, Hyacinthe Johnson-Ansah, Laurence Legros, Lydia Roy, Alain Delmer, Jean-Christophe Ianotto, Corentin Orvain, Fabrice Larosa, Mathieu Meunier, Shanti Amé, Annalisa Andreoli, Pascale Cony-Makhoul, Stéphane Morisset, Isabelle Tigaud, Delphine Rea, Franck Emmanuel Nicolini.

  Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.

Keywords:  ACA; Accelerated phase CML; BCR-ABL; TKI2

DOI:  https://doi.org/10.1016/j.leukres.2023.107308
Exp Hematol. 2023 May 24. pii: S0301-472X(23)00228-X. [Epub ahead of print]

Unifying targeted therapy for leukemia in the era of PARP inhibition.

Liberalis Debraj Boila, Amitava Sengupta.

  PARP inhibitors (PARPi) represent a novel class of targeted therapies that have conventionally been used for the treatment of BRCA1/2 mutated solid tumors. PARP1 being an indispensable component of the DNA repair machinery is essential for maintaining genomic integrity. Germline mutations or expression changes in genes compromising homologous recombination (HR) mediated repair increases dependency on PARP1 and sensitizes these cells to PARP inhibition. Unlike solid tumors, hematological malignancies do not frequently harbor BRCA1/2 mutations. PARP inhibition as a therapeutic strategy in blood disorders have therefore not been received the same importance. However, underlying epigenetic plasticity and leveraging transcriptional dependencies across molecular-subtypes of leukemia has invigorated PARP inhibition guided synthetic lethality in hematological malignancies. For example, recent studies showing importance of robust DNA repair machinery in acute myeloid leukemia (AML), increased evidence of genomic instability associated with leukemia driver mutations and compromised repair pathways in certain subgroups of AML has shifted the focus on exploiting PARPi synthetic lethality in leukemia. Single agent PARPi as well as combination with other targeted therapies has shown promising results in clinical trials involving AML and myelodysplasia patients. Here, we evaluate anti-leukemic potential of PARPi, understand subtype dependent differential responses, discuss recent clinical trials and provide an outlook for future combination therapy strategies. Extensive genetic and epigenetic characterization, utilizing results from completed and ongoing studies will further help to determine specific subset of patients who may respond, and establish PARPi as a mainstay in leukemia treatment.

Keywords:  AML epigenetics; Combination therapy; PARP, DNA repair; Reversion mutation

DOI:  https://doi.org/10.1016/j.exphem.2023.05.005
Blood Adv. 2023 May 26. pii: bloodadvances.2023009817. [Epub ahead of print]

Clonal Hematopoiesis in Survivors of Childhood Cancer.

Danielle Novetsky Friedman, Irenaeus Chi-Chung Chan, Chaya S Moskowitz, Shanita Li, Kimberly R Turner, Jie Liu, Nancy Bouvier, Michael F Walsh, Barbara Spitzer, Andrew L Kung, Michael Berger, Megan Anne Cooper, Iskra Pusic, Geoffrey L Uy, Daniel C Link, Todd E Druley, Luis A Diaz, Ross L Levine, Neerav Narendra Shukla, Kelly L Bolton.

DOI: https://doi.org/10.1182/bloodadvances.2023009817
Leukemia. 2023 May 26.

Genetic separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution.

Yulin Chen, Susanne Möbius, Konstantin Riege, Steve Hoffmann, Andreas Hochhaus, Thomas Ernst, Karl Lenhard Rudolph.

DOI: https://doi.org/10.1038/s41375-023-01929-6
Cancer Med. 2023 May 22.

Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry.

Teresa Bernal, Ainhoa Fernández Moreno, Almudena de LaIglesia, Celina Benavente, Ana García-Noblejas, Daniel García Belmonte, Rosalía Riaza, Olga Salamero, Maria Angeles Foncillas, Alicia Roldán, Víctor Noriega Concepción, Laura Llorente González, Juan Miguel Bergua Burgués, Soraya Lorente de Uña, Gabriela Rodríguez-Macías, Adolfo de la Fuente Burguera, Maria José García Pérez, Jose Luis López-Lorenzo, Pilar Martínez, Concepción Aláez, Marta Callejas, Carmen Martínez-Chamorro, José Rifón Roca, Lourdes Amador Barciela, Armando V Mena Durán, Karoll Gómez Correcha, Esperanza Lavilla Rubira, María Luz Amigo, Ferran Vall-Llovera, Ana Garrido, María García-Fortes, Dunia de Miguel Llorente, Anastasia Aules Leonardo, Carlos Cervero, Rosa Coll Jordá, Manuel M Pérez-Encinas, Marta Polo Zarzuela, Angela Figuera, Guillermo Rad, David Martínez-Cuadrón, Pau Montesinos.

   BACKGROUND: CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients.
METHODS: Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry.
RESULTS: Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62-71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18-0.59), p < 0.001.
CONCLUSION: Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.

Keywords:  acute myeloid leukemia; clinical observations; intensive chemotherapy; real-world

DOI:  https://doi.org/10.1002/cam4.6120
Curr Hematol Malig Rep. 2023 May 24.

Clonal Hematopoiesis in Myeloproliferative Neoplasms Confers a Predisposition to both Thrombosis and Cancer.

Tiziano Barbui, Antonello Gavazzi, Edoardo Sciatti, Maria Chiara Finazzi, Arianna Ghirardi, Greta Carioli, Alessandra Carobbio.

   PURPOSE OF REVIEW: This review focuses on vascular complications associated with chronic myeloproliferative neoplasms (MPN) and more specifically aims to discuss the clinical and biological evidence supporting the existence of a link between clonal hematopoiesis, cardiovascular events (CVE), and solid cancer (SC).
RECENT FINDINGS: The MPN natural history is driven by uncontrolled clonal myeloproliferation sustained by acquired somatic mutations in driver (JAK2, CALR, and MPL) and non-driver genes, involving epigenetic (e.g., TET2, DNMT3A) regulators, chromatin regulator genes (e.g., ASXL1, EZH2), and splicing machinery genes (e.g., SF3B1). The genomic alterations and additional thrombosis acquired risk factors are determinants for CVE. There is evidence that clonal hematopoiesis can elicit a chronic and systemic inflammation status that acts as driving force for the development of thrombosis, MPN evolution, and second cancer (SC). This notion may explain the mechanism that links arterial thrombosis in MPN patients and subsequent solid tumors. In the last decade, clonal hematopoiesis of indeterminate potential (CHIP) has been detected in the general population particularly in the elderly and initially found in myocardial infarction and stroke, rising the hypothesis that the inflammatory status CHIP-associated could confer predisposition to both cardiovascular diseases and cancer. In summary, clonal hematopoiesis in MPN and CHIP confer a predisposition to cardiovascular events and cancer through chronic and systemic inflammation. This acquisition could open new avenues for antithrombotic therapy both in MPNs and in general population by targeting both clonal hematopoiesis and inflammation.

Keywords:  Cancer; Clonal hematopoiesis of indeterminate potential; Disease progression; Inflammation; Myeloproliferative neoplasms; Thrombosis

DOI:  https://doi.org/10.1007/s11899-023-00697-5
Cell Mol Biol Lett. 2023 May 24. 28(1): 45

Deletion of CD36 exhibits limited impact on normal hematopoiesis and the leukemia microenvironment.

Yiting Meng, Mateusz Pospiech, Atham Ali, Ritu Chandwani, Mary Vergel, Sandra Onyemaechi, George Yaghmour, Rong Lu, Houda Alachkar.

   BACKGROUND: CD36 has been identified as a potential therapeutic target both in leukemic cells and in the tumor immune microenvironment. In acute myeloid leukemia (AML), we found that APOC2 acts with CD36 to promote leukemia growth by activating the LYN-ERK signaling. CD36 also plays a role in lipid metabolism of cancer associated T-cells leading to impaired cytotoxic CD8+ T-cell and enhanced Treg cell function. To establish CD36 as a viable therapeutic target in AML, we investigated whether targeting CD36 has any detrimental impact on normal hematopoietic cells.
METHODS: Differential expression data of CD36 during human and mouse normal hematopoiesis were examined and compared. Cd36 knockout (Cd36-KO) mice were evaluated for blood analysis, hematopoietic stem cells and progenitors (HSPCs) function and phenotype analyses, and T cells in vitro expansion and phenotypes in comparison with wild type (WT) mice. In addition, MLL-PTD/FLT3-ITD leukemic cells were engrafted into Cd36-KO and WT mice, and leukemia burden was compared between groups.
RESULTS: RNA-Seq data showed that Cd36 expression was low in HSPCs and increased as cells matured. Phenotypic analysis revealed limited changes in blood count except for a slight yet significantly lower red blood cell count and hemoglobin and hematocrit levels in Cd36-KO mice compared with WT mice (P < 0.05). In vitro cell proliferation assays of splenocytes and HSPCs from Cd36-KO mice showed a similar pattern of expansion to that of cells from WT mice. Characterization of HSPCs showed similar percentages of the different progenitor cell populations between Cd36-KO with WT mice. However, Cd36-KO mice exhibited ~ 40% reduction of the number of colonies developed from HSPCs cells compared with WT mice (P < 0.001). Cd36-KO and WT mice presented comparably healthy BM transplant in non-competitive models and developed similar leukemia burden.
CONCLUSIONS: Although the loss of Cd36 affects the hematopoietic stem cell and erythropoiesis, limited detrimental overall impact was observed on normal Hematopoietic and leukemic microenvironments. Altogether, considering the limited impact on normal hematopoiesis, therapeutic approaches to target CD36 in cancer are unlikely to result in toxicity to normal blood cells.

Keywords:  Acute myeloid leukemia; CD36; Hematopoiesis; Knockout; Mouse; T Cells

DOI:  https://doi.org/10.1186/s11658-023-00455-8
Br J Haematol. 2023 May 22.

Interferon alpha-2 treatment reduces circulating neutrophil extracellular trap levels in myeloproliferative neoplasms.

Laura Massarenti, Trine Alma Knudsen, Christian Enevold, Vibe Skov, Lasse Kjaer, Morten K Larsen, Thomas S Larsen, Dennis L Hansen, Hans C Hasselbalch, Claus H Nielsen.

  Neutrophil extracellular traps (NETs) may play a pathogenic role in the thrombosis associated with myeloproliferative neoplasms (MPNs). We measured serum NET levels in 128 pretreatment samples from patients with MPNs and in 85 samples taken after 12 months of treatment with interferon alpha-2 (PEG-IFNα-2) formulations or hydroxyurea (HU). No differences in NET levels were observed across subdiagnoses or phenotypic driver mutations. In PV, a JAK2V617F+ allele burden ≥50% associated with increased NET levels (p = 0.006). Baseline NET levels correlated with neutrophil count (r = 0.29, p = 0.001), neutrophil-to-lymphocyte ratio (r = 0.26, p = 0.004) and JAK2V617F allele burden (r = 0.22, p = 0.03), particularly in patients with PV and with allele burden ≥50% (r = 0.50, p = 0.01, r = 0.56, p = 0.002 and r = 0.45, p = 0.03 respectively). In PV, after 12 months of treatment, NET levels decreased on average by 60% in patients with allele burden ≥50%, compared to only 36% in patients with an allele burden <50%. Overall, treatment with PEG-IFNα-2a or PEG-IFNα-2b reduced NETs levels in 77% and 73% of patients, respectively, versus only 53% of HU-treated patients (average decrease across treatments: 48%). Normalization of blood counts did not per se account for these reductions. In conclusion, baseline NET levels correlated with neutrophil count, NLR and JAK2V617F allele burden, and IFNα was more effective at reducing prothrombotic NET levels than HU.

Keywords:   JAK2V617F ; interferon alpha (IFN-α); myeloproliferative neoplasm (MPN); neutrophil extracellular traps (NETs); thrombosis

DOI:  https://doi.org/10.1111/bjh.18845
Blood Sci. 2023 Apr;5(2): 101-105

Heterogeneity analysis of the CEBPAdm AML based on bZIP region mutations.

Yan Hui, Shuxin Li, Junping Zhang, Bingcheng Liu, Yingchang Mi, Hui Wei, Jianxiang Wang.

  Patients with double-mutated CEBPA (CEBPAdm) AML were stratified into favorable risk group, however, few studies have investigated the heterogeneity of different CEBPAdm types in detail. In this study, we analyzed 2211 newly diagnosed AML and identified CEBPAdm in 10.8% of the patients. Within the CEBPAdm cohort, 225 of 239 patients (94.14%) presented with bZIP region mutations (CEBPAdmbZIP) while 14 of 239 patients (5.86%) without bZIP region mutation (CEBPAdmnonbZIP). Analysis of the accompanied molecular mutations showed statistically different incidences of GATA2 mutations between the CEBPAdmbZIP group and the CEBPAdmnonbZIP group (30.29% vs 0%). In the analysis of outcomes, patients with CEBPAdmnonbZIP were associated with shorter overall survival (OS) censored at hematopoietic stem cell transplantation (HSCT) during CR1 compared to those with CEBPAdmbZIP (hazard ratio (HR) = 3.132, 95% confidence interval (CI) = 1.229-7.979, P = .017). Refractory or relapsed AML (R/RAML) patients with CEBPAdmnonbZIP were associated with shorter OS compared to those with CEBPAdmbZIP (HR = 2.881, 95% CI = 1.021-8.131, P = .046). Taken together, AML with CEBPAdmbZIP and CEBPAdmnonbZIP showed different outcomes and might be regarded as distinctive AML entities.

Keywords:  Acute myeloid leukemia; CEBPA mutations; Heterogeneity; Outcome

DOI:  https://doi.org/10.1097/BS9.0000000000000153
Blood Sci. 2023 Apr;5(2): 92-100

Role of the bone marrow vascular niche in chemotherapy for MLL-AF9-induced acute myeloid leukemia.

Chang Xu, Ting Lu, Xue Lv, Tao Cheng, Hui Cheng.

  Leukemia stem cells in acute myeloid leukemia (AML) can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy. In the context of AML, endothelial cells (ECs) are crucial components of these niches that appear to promote malignant expansion despite treatment. To better understand these interactions, we developed a real-time cell cycle-tracking mouse model of AML (Fucci-MA9) with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse. We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells, leading to relapse and proliferation. Importantly, post-chemotherapy resting leukemia cells tended to localize closer to blood vessels. Mechanistically, after chemotherapy, resting leukemia cells interacted with ECs, promoting their adhesion and anti-apoptotic capacity. Further, expression analysis of ECs and leukemia cells during AML, after chemotherapy, and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs. These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.

Keywords:  Acute myeloid leukemia; Bone marrow vascular microenvironment; Cell cycle; Chemotherapy

DOI:  https://doi.org/10.1097/BS9.0000000000000158
Blood Adv. 2023 May 26. pii: bloodadvances.2023009853. [Epub ahead of print]

Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease.

Monzr M Al Malki, Kaitlyn London, Janna Baez, Yu Akahoshi, William J Hogan, Aaron M Etra, Hannah K Choe, Elizabeth O Hexner, Amelia Langston, Sunil H Abhyankar, Doris M Ponce, Zachariah DeFilipp, Carrie L Kitko, Kehinde U A Adekola, Ran Reshef, Francis Ayuketang Ayuk, Alexandra Capellini, Chantiya Chanswangphuwana, Matthias Eder, Gilbert W Eng, Isha Gandhi, Stephan A Grupp, Sigrun Gleich, Ernst Holler, Nora Rebeka Javorniczky, Stelios Kasikis, Steven Kowalyk, George Morales, Umut Özbek, Wolf Rösler, Nikolaos Spyrou, Rachel Young, Gregory A Yanik, Yi-Bin Chen, Ryotaro Nakamura, James L M Ferrara, John E Levine.

GVHD of the gastrointestinal (GI) tract is the main cause of non-relapse mortality following allogeneic HCT. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA 2/3 scores correlate with resistance to treatment and higher non-relapse mortality (NRM). We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA 2/3 GVHD. Seventy-five evaluable patients were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events (AEs) in more than 10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared to 150 well matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58%; P=0.67 and 48% vs. 48%; P=1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39%, P=0.80 and 46% vs 54%, P=0.48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high risk GVHD.

DOI: https://doi.org/10.1182/bloodadvances.2023009853
Blood. 2023 May 22. pii: blood.2022019094. [Epub ahead of print]

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Qingsong Gao, Sarra L Ryan, Ilaria Iacobucci, Pankaj S Ghate, Ruth E Cranston, Claire J Schwab, Abdelrahman H Elsayed, Lei Shi, Stanley B Pounds, Shaohua Lei, Pradyumna Baviskar, Deqing Pei, Cheng Cheng, Matthew Bashton, Paul B Sinclair, David R Bentley, Mark Ross, Zoya Kingsbury, Terena James, Kathryn G Roberts, Meenakshi Devidas, Yiping Fan, Wenan Chen, Ti-Cheng Chang, Gang Wu, Andrew J Carroll, Nyla A Heerema, Virginia Valentine, Marcus B Valentine, Wenjian Yang, Jun J Yang, Anthony V Moorman, Christine J Harrison, Charles G Mullighan.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remain incompletely understood. Here, using integrated whole genome and transcriptome sequencing of 124 iAMP21-ALL patients, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL according to patterns of copy number alteration and structural variation. This large dataset enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which are differentially expressed compared to non-iAMP21-ALL cases, and including multiple genes implicated in the pathogenesis of acute leukemia: CHAF1B, DYRK1A, ERG, HMGN1 and RUNX1. Using multimodal single cell genomic profiling, including single cell whole genome sequencing of two cases, we documented clonal heterogeneity and genomic evolution, formally demonstrating that acquisition of the iAMP21-chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

DOI: https://doi.org/10.1182/blood.2022019094
Br J Haematol. 2023 May 21.

Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: A quantitative approach.

Japanese Society for Transplantation and Cellular Therapy (JSTCT)

  To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.

Keywords:  acute myeloid leukaemia; allogeneic stem cell transplantation; complex karyotype; monosomal karyotype

DOI:  https://doi.org/10.1111/bjh.18855
Blood. 2023 May 22. pii: blood.2022019304. [Epub ahead of print]

Prevalence and clinical expression of germline predisposition to myeloid neoplasms in adults with marrow hypocellularity.

Elisabetta Molteni, Elisa Bono, Anna Galli, Chiara Elena, Jacqueline Ferrari, Nicolas Fiorelli, Sara Pozzi, Virginia Valeria Ferretti, Martina Sarchi, Ettore Rizzo, Virginia Camilotto, Emanuela Boveri, Mario Cazzola, Luca Malcovati.

Systematic studies of germline genetic predisposition to myeloid neoplasms are still limited in adult patients. In this work, we performed germline and somatic targeted sequencing in a large cohort of adult patients with cytopenia and hypoplastic bone marrow to study germline predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted bone marrow cellularity. Germline mutation analysis was performed using a panel of 60 genes, and variants were interpreted according to the ACMG/AMP guidelines; somatic mutation analysis was performed using a panel of 54 genes. Twenty-seven out of 402 (6.7%) subjects carried germline variants causative of a predisposition syndrome/disorder. The most frequent predisposition disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germline genotype were diagnosed with myeloid neoplasm, whereas the remaining with cytopenia of undetermined significance. Subjects with predisposition syndrome/disorder were younger than the remaining ones (P=.03) and had higher risk of severe or multiple cytopenias and advanced myeloid malignancy (OR ranging from 2.51 to 5.58). In patients with myeloid neoplasm, causative germline mutations were associated with increased risk of progression into acute myeloid leukemia (HR=3.92, P=.008). Family history of cancer or personal history of multiple tumors, did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity and prevalence of germline predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic bone marrow.

DOI: https://doi.org/10.1182/blood.2022019304
Br J Haematol. 2023 May 21.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

Roisin Borrill, Kay Poulton, Laura Kusyk, Amy Routledge, Denise Bonney, Ramya Hanasoge-Nataraj, Madeleine Powys, Omima Mustafa, Helen Campbell, Srividhya Senthil, Richard Dillon, Jelena Jovanovic, Suzy Morton, Beki James, Kanchan Rao, Simon Stanworth, Joanne Konkel, Robert Wynn.

  In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

Keywords:  cord blood; cord blood transplant; granulocytes; myeloid leukaemia; paediatric haematology

DOI:  https://doi.org/10.1111/bjh.18863
Blood Adv. 2023 May 22. pii: bloodadvances.2023009806. [Epub ahead of print]

Pseudomonas aeruginosa ExoU-associated virulence in hematopoietic cell transplant and hematologic malignancy patients.

Lauren Fontana, Lynne Strasfeld, Morgan Hakki.

DOI: https://doi.org/10.1182/bloodadvances.2023009806
Br J Haematol. 2023 May 25.

Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression.

Zhixin Ma, Wenle Ye, Jinghan Wang, Xin Huang, Jiansong Huang, Xia Li, Chao Hu, Chenying Li, Yile Zhou, Xiangjie Lin, Wenwen Wei, Yu Qian, Yutong Zhou, Shihui Mao, Xiufeng Yin, Bo Zhu, Jie Jin.

  Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine-glutamate antiporter system Xc- . The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase-4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co-factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.

Keywords:  acute myeloid leukaemia; ferroptosis; glutamate dehydrogenase 1; glutathione

DOI:  https://doi.org/10.1111/bjh.18884
Nat Commun. 2023 May 22. 14(1): 2740

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.

Eva Crosas-Molist, Vittoria Graziani, Oscar Maiques, Pahini Pandya, Joanne Monger, Remi Samain, Samantha L George, Saba Malik, Jerrine Salise, Valle Morales, Adrien Le Guennec, R Andrew Atkinson, Rosa M Marti, Xavier Matias-Guiu, Guillaume Charras, Maria R Conte, Alberto Elosegui-Artola, Mark Holt, Victoria Sanz-Moreno.

Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

DOI: https://doi.org/10.1038/s41467-023-38292-0
J Clin Oncol. 2023 May 26. JCO2202366

Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.

Armin Rashidi, Maryam Ebadi, Tauseef Ur Rehman, Heba Elhusseini, David Kazadi, Hossam Halaweish, Mohammad H Khan, Andrea Hoeschen, Qing Cao, Xianghua Luo, Amanda J Kabage, Sharon Lopez, Shernan G Holtan, Daniel J Weisdorf, Alexander Khoruts, Christopher Staley.

PURPOSE: Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial.
METHODS: Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months.
RESULTS: In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister.
CONCLUSION: In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

DOI: https://doi.org/10.1200/JCO.22.02366
Blood Cell Ther. 2022 Dec 23. 5(Spec Edition): S25-S33

Advances in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia.

Yasuhito Nannya, Auro Viswabandya, Peihua Lu.

  In acute leukemia, advances have been made in therapeutic strategies centered on allogeneic hematopoietic stem cell transplantation (allo-SCT), three of which are presented here. The indication of allo-SCT for acute myeloid leukemia (AML) in 1st complete remission (CR1) has been debated. Genomic medicine has helped us gain a deeper understanding of this disease, some of which may serve as prognostic factors. Such genetic abnormalities could also help measure minimal residual disease (MRD) and provide additional clues to estimate the efficacy of chemotherapy. Combined with existing prognostic factors, these data can be used to construct a more accurate prognostic model, providing an optimal indication of allo-SCT for AML in CR1. Furthermore, overall treatment algorithms for high-risk AML after allo-SCT should include prophylactic and pre-emptive treatment to prevent relapse. These include immunotherapy using donor lymphocyte infusion (DLI), FLT3 inhibitors in FLT3-mutated AML, hypomethylating agents, or a combination of DLI with these agents. Clinical trials are currently ongoing to elucidate the role of these strategies, which will lead to a risk-adapted treatment for preventing relapse in high-risk AML. CD19-targeted chimeric antigen receptor (CAR) T-cell therapy induces a remarkable response in B-acute lymphoid leukemia (B-ALL); however, relapse remains a major problem. In this regard, allo-SCT as a consolidation treatment after CAR-T cell therapy for B-ALL is recommended for pediatric and adult patients. Achieving complete remission (CR) with CAR-T cell therapy is considered a promising bridging therapy to allo-SCT. Novel CAR-T treatment techniques are being developed to change their role as a pre-transplant treatment.

Keywords:  CAR-T; genomics; pre-emptive therapy; prophylaxis

DOI:  https://doi.org/10.31547/bct-2022-015