bims-tremyl 2023-09-03 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2023–09–03
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Phase II study of cladribine, idarubicin, and ara-C (CLIA) with or without sorafenib as initial therapy for patients with acute myeloid leukemia.
GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.
Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML:a randomized, placebo-controlled study by the ALLG.
Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets.
Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory acute myeloid leukemia.
Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based non-intensive therapy.
The Inflamed Niche: A Double-Edged Sword in AML?
IL-33-ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways.
Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.
Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis.
Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection.
TP53 status and impact on AML prognosis within the ELN 2022 risk classification.
DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia.
Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia.
Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study.
Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.
A non-coding m6A reader promotes leukaemia.
An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.
Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.
Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT.
Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy.
Allogeneic hematopoietic stem cell transplantation for adults with therapy-related acute myeloid leukaemia: a retrospective multicentre study on behalf of the SFGM-TC.
Myeloid lineage switch in KMT2A-rearranged acute lymphoblastic leukemia treated with lymphoid lineage-directed therapies.
Structural basis of PML/RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function.
Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.
Chronic inflammation can transform the fate of normal and mutant haematopoietic stem cells.
A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
How I treat transplant-eligible patients with myelofibrosis.
Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.
Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment.

Am J Hematol. 2023 Aug 27.

Phase II study of cladribine, idarubicin, and ara-C (CLIA) with or without sorafenib as initial therapy for patients with acute myeloid leukemia.

Tapan M Kadia, Farhad Ravandi, Matteo Molica, Alex Bataller, Gautam Borthakur, Naval Daver, Elias Jabbour, Courtney D DiNardo, Naveen Pemmaraju, Nitin Jain, Alessandra Ferrajoli, Musa Ylimaz, Prithviraj Bose, Rebecca Slack Tidwell, Kayleigh R Marx, Caitlin R Rausch, Rashmi Kanagal-Shamanna, Sa Wang, Rabiul Islam, Richard Champlin, Elizabeth Shpall, Marina Konopleva, Guillermo Garcia-Manero, Hagop Kantarjian.

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.

DOI: https://doi.org/10.1002/ajh.27054
Blood Adv. 2023 Aug 28. pii: bloodadvances.2023010460. [Epub ahead of print]

GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.

Yu Wei Zhang, Talia Velasco-Hernandez, Julian Mess, Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Nadine Obier, Nikolaos Karantzelis, Jasmin Rettkowski, Katharina Schönberger, Noémie Karabacz, Karin Jäcklein, Tatsuya Morishima, Juan Luis Trincado, Paola Romecin, Alba Martinez-Moreno, Hitoshi Takizawa, Khalid Shoumariyeh, Simon Renders, Robert Zeiser, Heike L Pahl, François Béliveau, Josée Hébert, Bernhard Lehnertz, Guy Sauvageau, Pablo Menendez, Nina Cabezas-Wallscheid.

Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong anti-leukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow (BM) cells. This anti-leukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.

DOI: https://doi.org/10.1182/bloodadvances.2023010460
Blood. 2023 Aug 30. pii: blood.2023020301. [Epub ahead of print]

Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML:a randomized, placebo-controlled study by the ALLG.

Sun Loo, Andrew W Roberts, Natasha S Anstee, Glen A Kennedy, Simon Zhao-Xiong He, Anthony P Schwarer, Anoop Kumar Enjeti, James D'Rozario, Paula Marlton, Ian Bilmon, John M Taper, Gavin Cull, Campbell Tiley, Emma Verner, Uwe Hahn, Devendra K Hiwase, Harry J Iland, Nicholas Edward Murphy, Sundra Ramanathan, John Reynolds, Doen Ming Ong, Ing Soo Tiong, Meaghan Wall, Michael Murray, Tristan Rawling, Joanna Leadbetter, Leesa Rowley, Maya Latimer, Sam L S Yuen, Stephen B Ting, Chun Yew Fong, Kirk Lachlan Morris, Ashish Bajel, John F Seymour, Mark J Levis, Andrew H Wei.

Sorafenib maintenance improves outcome after hematopoietic cell transplant (HCT) for patients with FLT3-ITD acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients 18-65 years (2:1) to sorafenib vs placebo (days 4-10) combined with intensive induction; idarubicin 12mg/m2 days 1-3 plus cytarabine 1.5g/m2 twice daily on days 1,3,5,7 (18-55 years) or 100mg/m2 days 1-7 (56-65 years), consolidation therapy, followed by maintenance treatment for 12 months (post-HCT excluded) in newly diagnosed FLT3-ITD AML. Four patients were excluded from modified intention-to-treat final analysis (3 not dosed and 1 later found to be FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery (CR/CRi) were high in both arms (sorafenib 78%/9%, placebo 70%/24%). With 49.1 months median follow-up, the primary endpoint of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%)(hazard ratio [HR] 0.87;95% confidence interval [CI] 0.51-1.51, p=0.61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR 0.76; 95% CI 0.42-1.39). For patients transplanted in first remission, 2-year OS was 84% and 67% in the sorafenib and placebo arms, respectively (HR 0.45;95% CI 0.18-1.12, p=0.08). In exploratory analyses, FLT3-ITD measurable residual disease negative status (<0.001%) post-induction was associated with improved 2-year OS (83% vs 60%) (HR 0.4;95% CI 0.17-0.93, p=0.028). In conclusion, routine use of pre-transplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

DOI: https://doi.org/10.1182/blood.2023020301
Leukemia. 2023 Aug 26.

Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets.

Minako Mori, Yasuo Kubota, Arda Durmaz, Carmelo Gurnari, Charnise Goodings, Vera Adema, Ben Ponvilawan, Waled S Bahaj, Tariq Kewan, Thomas LaFramboise, Manja Meggendorfer, Claudia Haferlach, John Barnard, Marcin Wlodarski, Valeria Visconte, Torsten Haferlach, Jaroslaw P Maciejewski.

Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.

DOI: https://doi.org/10.1038/s41375-023-02003-x
Blood Adv. 2023 Aug 30. pii: bloodadvances.2023010956. [Epub ahead of print]

Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory acute myeloid leukemia.

Farhad Ravandi, Asad Bashey, James M Foran, Wendy Stock, Raya Mawad, Nicholas J Short, Musa Yilmaz, Hagop M Kantarjian, Olatoyosi Odenike, Anand A Patel, Raman Garcha, William Barrett Ainsworth, Raphael Clynes, Jitendra Kanodia, Ying Ding, Huajiang Li, Steve Kye, Alice S Mims.

Acute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This Phase 1 study's primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended Phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response syndrome (CRS), followed by weekly dosing (1.7 µg/kg, Cohort -1D). In 16/120 patients, at least 1 treatment-emergent adverse event was classified as a dose-limiting toxicity. CRS, the most common adverse event (59.2%), managed with premedication, were mostly ≤Grade 2. A secondary objective was assessment of efficacy in patients with CD123 expressing leukemias. A total of 10/111 (9.0%) efficacy-evaluable AML patients achieved an overall response of morphologic leukemia free state or better with an overall objective response rate (ORR) of 9.0%. Response was only observed in patients receiving a target dose of 0.75 µg/kg or higher (n = 87) in which the efficacy-evaluable ORR was 11.5%. Response was associated with lower baseline blast count in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312.

DOI: https://doi.org/10.1182/bloodadvances.2023010956
Blood. 2023 Aug 30. pii: blood.2023021579. [Epub ahead of print]

Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based non-intensive therapy.

Jad Othman, Ing Soo Tiong, Jenny O'Nions, Mike Dennis, Katya Mokretar, Adam Ivey, Michael James Austin, Annie-Louise Latif, Mariam Amer, Wei Yee Chan, Charles R Crawley, Francesca Crolla, Joe Wilson Cross, Raymond Dang, Johnathon Elliot, Chun Yew Fong, Sofia Galli, Paolo Gallipoli, Francesca Hogan, Pallavi Kalkur, Anjum Bashir Khan, Pramila Krishnamurthy, John Laurie, Sun Loo, Scott Marshall, Priyanka Mehta, Vidhya Murthy, Sateesh Nagumantry, Srinivas Pillai, Nicola Potter, Rob S Sellar, Tom Taylor, Rui Zhao, Nigel H Russell, Andrew H Wei, Richard Dillon.

Assessment of measurable residual disease (MRD) by RT-qPCR is strongly prognostic in patients with NPM1-mutated AML treated with intensive chemotherapy, however there are no data regarding its utility in venetoclax-based non-intensive therapy, despite high efficacy in this genotype. We analysed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved CR/CRi following treatment with venetoclax and hypomethylating agents (HMA) or low dose cytarabine (LDAC). 44 patients (58%) achieved bone marrow (BM) MRD negativity and a further 14 (18%) a reduction of ≥4 log10 from baseline as their best response, with no difference between HMA and LDAC. The cumulative rate of BM MRD negativity by the end of cycles 2, 4 and 6 was 25%, 47% and 50%. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall (OS) of 84% compared to 46% if MRD positive. On multivariable analyses MRD negativity was the strongest prognostic factor. 22 patients electively stopped therapy in BM MRD negative remission after a median of 8 cycles with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

DOI: https://doi.org/10.1182/blood.2023021579
Blood Cancer Discov. 2023 Sep 01. 4(5): 349-351

The Inflamed Niche: A Double-Edged Sword in AML?

Livia E Lisi-Vega, Simón Méndez-Ferrer.

SUMMARY: Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack. See related article by Chen et al., p. 394 (7) .

DOI: https://doi.org/10.1158/2643-3230.BCD-23-0125
Sci Signal. 2023 Aug 29. 16(800): eadd7705

IL-33-ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways.

Pascal Naef, Ramin Radpour, Carla A Jaeger-Ruckstuhl, Nils Bodmer, Gabriela M Baerlocher, Hartmut Doehner, Konstanze Doehner, Carsten Riether, Adrian F Ochsenbein.

Cell stemness is characterized by quiescence, pluripotency, and long-term self-renewal capacity. Therapy-resistant leukemic stem cells (LSCs) are the primary cause of relapse in patients with chronic and acute myeloid leukemia (CML and AML). However, the same signaling pathways frequently support stemness in both LSCs and normal hematopoietic stem cells (HSCs), making LSCs difficult to therapeutically target. In cell lines and patient samples, we found that interleukin-33 (IL-33) signaling promoted stemness only in leukemia cells in a subtype-specific manner. The IL-33 receptor ST2 was abundant on the surfaces of CD34+ BCR/ABL1 CML and CD34+ AML cells harboring AML1/ETO and DEK/NUP214 translocations or deletion of chromosome 9q [del(9q)]. The cell surface abundance of ST2, which was lower or absent on other leukemia subtypes and HSCs, correlated with stemness, activated Wnt signaling, and repressed Notch signaling. IL-33-ST2 signaling promoted the maintenance and expansion of AML1/ETO-, DEK/NUP214-, and BCR/ABL1-positive LSCs in culture and in mice by activating Wnt, MAPK, and NF-κB signaling. Wnt signaling and its inhibition of the Notch pathway up-regulated the expression of the gene encoding ST2, thus forming a cell-autonomous loop. IL-33-ST2 signaling promoted the resistance of CML cells to the tyrosine kinase inhibitor (TKI) nilotinib and of AML cells to standard chemotherapy. Thus, inhibiting IL-33-ST2 signaling may target LSCs to overcome resistance to chemotherapy or TKIs in these subtypes of leukemia.

DOI: https://doi.org/10.1126/scisignal.add7705
Nature. 2023 Aug 30.

Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.

Gabriele Casirati, Andrea Cosentino, Adele Mucci, Mohammed Salah Mahmoud, Iratxe Ugarte Zabala, Jing Zeng, Scott B Ficarro, Denise Klatt, Christian Brendel, Alessandro Rambaldi, Jerome Ritz, Jarrod A Marto, Danilo Pellin, Daniel E Bauer, Scott A Armstrong, Pietro Genovese.

Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3-5. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.

DOI: https://doi.org/10.1038/s41586-023-06496-5
Nat Commun. 2023 Sep 01. 14(1): 5325

Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis.

Bin Zhang, Dandan Zhao, Fang Chen, David Frankhouser, Huafeng Wang, Khyatiben V Pathak, Lei Dong, Anakaren Torres, Krystine Garcia-Mansfield, Yi Zhang, Dinh Hoa Hoang, Min-Hsuan Chen, Shu Tao, Hyejin Cho, Yong Liang, Danilo Perrotti, Sergio Branciamore, Russell Rockne, Xiwei Wu, Lucy Ghoda, Ling Li, Jie Jin, Jianjun Chen, Jianhua Yu, Michael A Caligiuri, Ya-Huei Kuo, Mark Boldin, Rui Su, Piotr Swiderski, Marcin Kortylewski, Patrick Pirrotte, Le Xuan Truong Nguyen, Guido Marcucci.

The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.

DOI: https://doi.org/10.1038/s41467-023-41167-z
J Exp Clin Cancer Res. 2023 Aug 31. 42(1): 223

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection.

Francesca Liccardo, Martyna Śniegocka, Claudia Tito, Alessia Iaiza, Tiziana Ottone, Mariadomenica Divona, Serena Travaglini, Maurizio Mattei, Rosella Cicconi, Selenia Miglietta, Giuseppe Familiari, Stefania Annarita Nottola, Vincenzo Petrozza, Luca Tamagnone, Maria Teresa Voso, Silvia Masciarelli, Francesco Fazi.

   BACKGROUND: Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A).
METHODS: We treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML.
RESULTS: The combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs.
CONCLUSIONS: Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling.

Keywords:  AML; Actin cytoskeleton; Bone marrow stromal cells; ER stress; Oxidative stress; Proteotoxic stress; Tumor microenvironment; YAP

DOI:  https://doi.org/10.1186/s13046-023-02793-z
Blood. 2023 Aug 30. pii: blood.2023020855. [Epub ahead of print]

TP53 status and impact on AML prognosis within the ELN 2022 risk classification.

Shaun A Fleming, Xavier Cheng-Hong Tsai, Rhiannon Morris, Hsin-An Hou, Andrew H Wei.

This study reports 1) frequency of TP53 co-mutation within each component of the ELN 2022 AML risk classification, 2) relevance of TP53 mut VAF<10%, 3) prognostic impact of -7, -5/del(5q), -17/abn(17p), CK/MK or myelodysplasia related gene mutations with/without mutated TP53.

DOI: https://doi.org/10.1182/blood.2023020855
Blood Adv. 2023 Aug 30. pii: bloodadvances.2023010337. [Epub ahead of print]

DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia.

Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary L Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David Brian Sykes.

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.

DOI: https://doi.org/10.1182/bloodadvances.2023010337
Cell Death Dis. 2023 08 29. 14(8): 573

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia.

Chendi Xie, Hui Zhou, Dongmei Qin, Huijian Zheng, Yuanfang Tang, Wenjuan Li, Jie Zhou, Long Liu, Xinxin Yu, Hongpeng Duan, Yong Zhou, Zhifeng Li, Zhihong Fang, Yiming Luo, Bing Z Carter, Bing Xu, Jie Zha.

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.

DOI: https://doi.org/10.1038/s41419-023-06075-6
Am J Hematol. 2023 Aug 30.

Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study.

Giovanni Paolo Maria Zambrotta, Franck E Nicolini, Sarit Assouline, Lambert Busque, Ester Pungolino, Elisabetta Abruzzese, Maria Cristina Miggiano, Chiara Elena, Alberto Alvarez-Larran, Ana Triguero, Alessandra Iurlo, Cristina Bucelli, Marco Cerrano, Isabella Capodanno, Francesca Lunghi, Philipp le Coutre, Sara Galimberti, Giovanni Caocci, Margherita Maffioli, Fabio Stagno, Susanne Saussele, Rocco Piazza, Brian J Druker, Carmen Fava, Veronica Guglielmana, Federica Colombo, Laura Antolini, Carlo Gambacorti-Passerini.

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.

DOI: https://doi.org/10.1002/ajh.27073
Cancer. 2023 Sep 01.

Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Sebastian Giebel, Myriam Labopin, Urpu Salmenniemi, Gerard Socié, Sergey Bondarenko, Didier Blaise, Nicolaus Kröger, Jan Vydra, Anna Grassi, Francesca Bonifazi, Tomasz Czerw, Achilles Anagnostopoulos, Bruno Lioure, Annalisa Ruggeri, Bipin Savani, Alexandros Spyridonidis, Jaime Sanz, Zinaida Peric, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.

   BACKGROUND: The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors.
METHODS: Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43 years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL.
RESULTS: In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2 years was reduced in the PTCY group (18% vs. 25%; p = .046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p = .29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p = .01), and 82% versus 74%, respectively (p = .08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p = .04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p = .045).
CONCLUSIONS: The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.

Keywords:  acute lymphoblastic leukemia; allogeneic hematopoietic cell transplantation; antithymocyte globulin; cyclophosphamide; matched unrelated donor; relapse; survival

DOI:  https://doi.org/10.1002/cncr.35004
Nat Cell Biol. 2023 Aug 28.

RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.

Xiaoyang Dou, Yu Xiao, Chao Shen, Kitty Wang, Tong Wu, Chang Liu, Yini Li, Xianbin Yu, Jun Liu, Qing Dai, Kinga Pajdzik, Chang Ye, Ruiqi Ge, Boyang Gao, Jianhua Yu, Shuying Sun, Mengjie Chen, Jianjun Chen, Chuan He.

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

DOI: https://doi.org/10.1038/s41556-023-01213-w
Nat Cell Biol. 2023 Aug 28.

A non-coding m6A reader promotes leukaemia.

James Russell, Konstantinos Tzelepis.

DOI: https://doi.org/10.1038/s41556-023-01205-w
Curr Hematol Malig Rep. 2023 Aug 31.

An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.

Nicholas J Short, Jayastu Senapati, Elias Jabbour.

   PURPOSE OF REVIEW: While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management.
RECENT FINDINGS: Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of allogeneic stem cell transplantation is controversial in CML-AP but has consistently been shown to improve outcomes for patients with CML-BP. Advanced phase CML, particularly CML-BP, remains a poor risk subtype of CML. However, novel combination approaches using later-generation TKIs are being explored in clinical trials and may lead to improved outcomes.

Keywords:  Accelerated phase CML; BCR::ABL1; Blast phase CML; Chronic myeloid leukemia; Philadelphia chromosome; Ponatinib

DOI:  https://doi.org/10.1007/s11899-023-00709-4
Acta Pharmacol Sin. 2023 Aug 29.

Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

Wen-Xiang Ren, Hao Guo, Sheng-Yan Lin, Si-Yi Chen, Yao-Ying Long, Liu-Yue Xu, Di Wu, Yu-Lin Cao, Jiao Qu, Bian-Lei Yang, Hong-Pei Xu, He Li, Ya-Li Yu, An-Yuan Zhang, Shan Wang, Yi-Cheng Zhang, Ke-Shu Zhou, Zhi-Chao Chen, Qiu-Bai Li.

  Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

Keywords:  ABT-199; CYTH1; MCL1; SecinH3; acute myeloid leukemia; cell adhesion

DOI:  https://doi.org/10.1038/s41401-023-01142-2
Bone Marrow Transplant. 2023 Aug 28.

Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT.

Jia Chen, Myriam Labopin, Thomas Pabst, Xi Zhang, Erlie Jiang, Alessandra Tucci, Jan Cornelissen, Ellen Meijer, Irma Khevelidze, Emmanuelle Polge, Depei Wu, Mohamad Mohty, Norbert-Claude Gorin.

In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.

DOI: https://doi.org/10.1038/s41409-023-02070-9
Leuk Res. 2023 Aug 22. pii: S0145-2126(23)00639-2. [Epub ahead of print]133 107374

Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy.

Fatima M Khadadah, Sonia Cerquozzi, Harold J Olney, Christina Fraga, Jill Dudebout, Anargyros Xenocostas, Nicholas Finn, Vincent Ethier, M Lynn Savoie, Lambert Busque, Kareem Jamani, Philip Kuruvilla, Carolyn Faught, Brian Leber, Rayan Kaedbey, Sarit E Assouline, Dennis Kim.

   BACKGROUND: Asciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein.
METHODS: Forty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data.
RESULTS: The median age was 60 years (range 17-90) with a past history of a cardiovascular event in 21 patients (51%). Patients were pretreated with a median of 3 previous tyrosine kinase inhibitors (range 1-5). After a median of 12 months of asciminib (range 3-41), major molecular response (MMR) rate was 39% (n = 11/28) and 42% (n = 5/12) at 6 and 12 months, respectively. Molecular response with 2 log reduction (MR2) was noted in 54% (n = 15/28) and 50% (n = 6/12) at 6 and 12 months. The cumulative incidence of MMR and MR2 was 46.3% and 66% at 12 months. Five patients discontinued asciminib due to treatment failure (n = 3) or thrombocytopenia (n = 2). There were no cardiovascular events. Out of 7 patients treated with high dose asciminib for T315I mutation, 5 patients achieved MMR or deeper response. The event-free survival was 63% at 12 months.
CONCLUSION: This study confirmed clinical efficacy and tolerability of asciminib with real-world experience.

Keywords:  Asciminib; Chronic myeloid leukemia; Real-world evidence; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1016/j.leukres.2023.107374
Bone Marrow Transplant. 2023 Aug 31.

Allogeneic hematopoietic stem cell transplantation for adults with therapy-related acute myeloid leukaemia: a retrospective multicentre study on behalf of the SFGM-TC.

Gaëlle Rey, Elisabeth Daguenet, Paul Bonjean, Raynier Devillier, Nathalie Fegueux, Edouard Forcade, Micha Srour, Patrice Chevallier, Marie Robin, Felipe Suarez, Jean-Baptiste Micol, Hélène Labussière-Wallet, Karin Bilger, Etienne Daguindau, Jacques-Olivier Bay, Amandine Fayard, Claude-Eric Bulabois, Stéphanie Nguyen-Quoc, Alexis Genthon, Corentin Orvain, Pascal Turlure, Michael Loschi, Xavier Poiré, Gaëlle Guillerm, Yves Beguin, Natacha Maillard, Jean-Baptiste Mear, Emilie Chalayer, Jérôme Cornillon, Emmanuelle Tavernier.

We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukaemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or breast (34%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9-52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6-67.5), 52.8% (95% CI 46.5-68.4), and 44.1% (95% CI 37.6-51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4-52.1), 40.4% (95% CI 33.9-48.1), and 35.3% (95% CI 28.8-43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 21% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.

DOI: https://doi.org/10.1038/s41409-023-02082-5
Haematologica. 2023 Aug 31.

Myeloid lineage switch in KMT2A-rearranged acute lymphoblastic leukemia treated with lymphoid lineage-directed therapies.

Alex Bataller, Tareq Abuasab, David McCall, Wei Wang, Branko Cuglievan, Ghayas C Issa, Elias Jabbour, Nicholas Short, Courtney D DiNardo, Guilin Tang, Guillermo Garcia-Manero, Hagop M Kantarjian, Koji Sasaki.

Not available.

DOI: https://doi.org/10.3324/haematol.2023.283705
Cancer Discov. 2023 Sep 01.

Structural basis of PML/RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function.

Pierre Bercier, Qian Qian Wang, Ning Zang, Jie Zhang, Chang Yang, Yasen Maimaitiyiming, Majdouline Abou-Ghali, Caroline Berthier, Chengchen Wu, Michiko Niwa-Kawakita, Thassadite Dirami, Marie-Claude Geoffroy, Omar Ferhi, Samuel Quentin, Shirine Benhenda, Yasumitsu Ogra, Zoher Gueroui, Chun Zhou, Hua Naranmandura, Hugues de The, Valerie Lallemand-Breitenbach.

PML Nuclear Bodies (NBs) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% APL patients, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB-assembly, PML sumoylation and PML-RARA degradation, mechanistically explaining clinical ATO-resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML which could pave the way to novel cancer drugs.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0453
bioRxiv. 2023 Aug 19. pii: 2023.08.17.553736. [Epub ahead of print]

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Paul V Dellorusso, Melissa A Proven, Fernando J Calero-Nieto, Xiaonan Wang, Carl A Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W Swann, Theodore T Ho, Zhiyu Zhao, Sean C Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué.

Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( 1 ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( 2 ), and for HSC function and response to nutrient stress ( 3,4 ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( 4 ). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche ( 5 ). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.
One-Sentence Summary: Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.

DOI: https://doi.org/10.1101/2023.08.17.553736
Cell. 2023 Aug 22. pii: S0092-8674(23)00852-8. [Epub ahead of print]

Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.

Naotaka Tsutsumi, Zahra Masoumi, Sophie C James, Julie A Tucker, Hauke Winkelmann, William Grey, Lora K Picton, Lucie Moss, Steven C Wilson, Nathanael A Caveney, Kevin M Jude, Cornelius Gati, Jacob Piehler, Ian S Hitchcock, K Christopher Garcia.

  Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPOmod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPOmod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPOmod in hematology research and clinical HSC transplantation.

Keywords:  JAK-STAT; TpoR; c-MPL; cryo-EM; hematopoiesis; ligand engineering; mTOR; signaling; structure; thrombopoietin

DOI:  https://doi.org/10.1016/j.cell.2023.07.037
Exp Hematol. 2023 Aug 28. pii: S0301-472X(23)01697-1. [Epub ahead of print]

Chronic inflammation can transform the fate of normal and mutant haematopoietic stem cells.

Jingjing Li, Camille Malouf, Linde A Miles, Mara B Willis, Eric M Pietras, Katherine Y King.

Chronic inflammation, while subtle, puts the body in a constant state of alert and is associated with a number of diseases, including cancer and cardiovascular diseases. It leads hematopoietic cells to produce and release pro-inflammatory cytokines, which trigger specific signalling pathways in hematopoietic stem cells (HSCs) that cause changes in proliferation, differentiation, and migration. This response is essential when HSCs are needed to produce specific blood cells to eliminate an intruder, such as a pathogenic virus, but mutant HSCs can use these pro-inflammatory signals to their advantage and accelerate the development of haematological disease or malignancy. Understanding this complex process is vital in monitoring and controlling disease progression in patients. In the 2023 Winter International Society for Experimental Hematology (ISEH) webinar, Dr. Eric Pietras (University of Colorado Anschutz Medical Campus, USA) and Dr. Katherine Y. King (Baylor College of Medicine, USA) gave a presentation on this topic, which is summarized in this review article.

DOI: https://doi.org/10.1016/j.exphem.2023.08.008
Nat Metab. 2023 Aug 31.

A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.

Undiagnosed Diseases Network

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.

DOI: https://doi.org/10.1038/s42255-023-00873-0
Blood. 2023 Aug 30. pii: blood.2023021218. [Epub ahead of print]

How I treat transplant-eligible patients with myelofibrosis.

Nicolaus Kröger, Christine Wolschke, Nico Gagelmann.

Despite approval of JAK inhibitors and novel agents for patients with myelofibrosis (MF), disease-modifying responses remain limited and hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment option. Numbers of HSCT continue to increase worldwide for MF, but its inherent therapy-related morbidity and mortality limit its use for many patients. Furthermore, MF patients often present at older age, with cytopenia, splenomegaly, and severe bone marrow fibrosis, posing challenges in managing these patients throughout the whole HSCT procedure. Although implementation of molecular analyses enabled improved understanding of disease mechanisms and subsequently sparked development of novel drugs with promising activity, prospective trials in the HSCT setting are often lacking, making an evidence-based decision process particularly difficult. To illustrate how we approach MF patients with respect to HSCT, we present 3 different clinical scenarios to capture relevant aspects that influence our decision-making regarding indication for or against HSCT. We will describe how we perform HSCT according to different risk and furthermore discuss our up-to-date approach to reduce transplant-related complications. Last, we will show how to harness graft-versus-MF effects particularly in the post-transplant period to achieve the best possible outcomes for patients.

DOI: https://doi.org/10.1182/blood.2023021218
JACC Heart Fail. 2023 Aug 21. pii: S2213-1779(23)00509-7. [Epub ahead of print]

Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.

Maurits A Sikking, Sophie L V M Stroeks, Michiel T H M Henkens, Anne G Raafs, Benjamin Cossins, Rosanne C van Deuren, Marlies Steehouwer, Niels P Riksen, Arthur van den Wijngaard, Han G Brunner, Alexander Hoischen, Job A J Verdonschot, Stephane R B Heymans.

   BACKGROUND: Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation, and thereby impact the disease course in atherosclerosis and ischemic heart failure. Clonal hematopoiesis of indeterminate potential (CHIP) refers to a variant allele frequency (VAF; a marker for clone size) in blood of ≥2%. The impact of CH clones -including small clone sizes (VAF<0.5%)- in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined.
OBJECTIVES: To establish the prognostic impact of CH in DCM including small clones.
METHODS: CH is determined using an ultrasensitive single-molecule Molecular Inversion Probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were analyzed using receiver operating characteristic curve-optimized VAF cut-off values.
RESULTS: Five hundred twenty DCM patients have been included. One hundred and nine patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 <0.5%. The median follow-up duration is 6.5 years [interquartile range 4.7-9.7]. DCM patients with CH have a higher risk of cardiac death (HR 2.33 using a VAF cut-off of 0.36%, 95% confidence interval 1.24-4.40) and all-cause mortality (HR 1.72 using a VAF cut-off of 0.06%, 95% confidence interval 1.10-2.69), independent of age, sex, left ventricle ejection fraction and New York Heart Association classification.
CONCLUSION: CH predicts cardiac death and all-cause mortality in DCM patients with an optimal threshold for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant independent of clone size in patients with DCM.

Keywords:  clonal hematopoiesis; dilated cardiomyopathy; heart failure

DOI:  https://doi.org/10.1016/j.jchf.2023.06.037
Leukemia. 2023 Aug 26.

Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment.

PROUD-PV Study Group

DOI: https://doi.org/10.1038/s41375-023-02008-6