bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–12–31
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
  2. Acute lymphoblastic leukemia with myeloid mutations is a high-risk disease associated with clonal hematopoiesis.
  3. High risk and silent clonal hematopoietic genotypes in patients with non-hematologic cancer.
  4. Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation.
  5. The clinical, molecular, and prognostic features of the 2022 WHO and ICC classification systems for myelodysplastic neoplasms.
  6. Distinct clinico-molecular arterial and venous thrombosis scores for myeloproliferative neoplasms risk stratification.
  7. CBFB::MYH11 fusion in a nonmonocytic acute myeloid leukemia.
  8. Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.
  9. TNF alpha promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.
  10. TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.
  11. Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
  12. Jak2V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross-talk.
  13. Recent advances in ex vivo expansion of human hematopoietic stem cells.
  14. Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice.
  15. In vitro evidence of synergistic efficacy with asciminib combined with reduced dose of ATP-binding pocket tyrosine kinase inhibitors according to the ABL1 kinase domain mutation profile.
  16. LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia.
  17. Nucleic Acid-Induced Inflammation on Hematopoietic Stem Cells.
  18. Toward an anatomy of human hematopoiesis.
  19. Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
  20. Gilteritinib in peritransplant period for relapsed or refractory FLT3-mutated acute myeloid leukemia: A case report of three patients.
  21. How to improve treatment-free remission eligibility in chronic myeloid leukaemia?
  22. Association between elevated white blood cell counts and thrombotic events in polycythemia vera: Analysis from REVEAL.
  23. Decreased patency of transjugular intrahepatic portosystemic shunts performed for splanchnic vein thrombosis in patients with myeloproliferative neoplasms.
  1. Leukemia. 2023 Dec 26.
    Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
    Hiroki Akiyama, Ran Zhao, Lauren B Ostermann, Ziyi Li, Matthew Tcheng, Samar J Yazdani, Arman Moayed, Malcolm L Pryor, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R Ruvolo, Bing Z Carter, Aaron D Schimmer, Michael Andreeff, Jo Ishizawa.
      Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.
    DOI:  https://doi.org/10.1038/s41375-023-02117-2
  2. Blood Cancer Discov. 2023 Dec 27.
    Acute lymphoblastic leukemia with myeloid mutations is a high-risk disease associated with clonal hematopoiesis.
    Caner Saygin, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S Sperling, Lachelle D Weeks, Marlise R Luskin, Todd C Knepper, Pankhuri Wanjari, Peng Wang, Angela M Lager, Carrie Fitzpatrick, Jeremy P Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X Cheng, Bart J Eisfelder, Oliver Bohorquez, Anand A Patel, Sheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M Odenike, Richard A Larson, Lucy A Godley, Daniel A Arber, Christopher J Gibson, Nikhil C Munshi, Guido Marcucci, Benjamin L Ebert, John M Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D Shah, Wendy Stock.
      Myeloid neoplasms arise from pre-existing clonal hematopoiesis (CH), however the role of CH in pathogenesis of ALL is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single cell RNA-sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0106
  3. Blood Adv. 2023 Dec 26. pii: bloodadvances.2023011262. [Epub ahead of print]
    High risk and silent clonal hematopoietic genotypes in patients with non-hematologic cancer.
    Aaron James Stonestrom, Kamal N Menghrajani, Sean M Devlin, Sebastià Franch-Expósito, Ryan N Ptashkin, Swara Y Patel, Barbara Spitzer, Xiaodi Wu, Justin Jee, Pablo Sánchez Vela, Jennifer Milbank, Ronak H Shah, Abhinita S Mohanty, Rose Rose Brannon, Wenbin Xiao, Michael F Berger, Simon Mantha, Ross L Levine.
      Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) >= 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy we analyzed data from 42,714 patients who underwent blood sequencing as a normal comparator for non-hematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and non-coding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset while DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of non-hematologic cancer.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011262
  4. Blood Adv. 2023 Dec 26. pii: bloodadvances.2022008926. [Epub ahead of print]
    Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation.
    Stijn N R Fuchs, Ursula S A Stalmann, Inge A M Snoeren, Eric Bindels, Stephani Schmitz, Bella Banjanin, Remco Hoogenboezem, Stanley van Herk, Mohamed Saad, Wencke Walter, Torsten Haferlach, Lancelot Seillier, Julio Saez-Rodriguez, Aurelien J F Dugourd, Kjong-Van Lehmann, Y Ben-Neriah, Hélène F E Gleitz, Rebekka K Schneider.
      It is still not fully understood how genetic haploinsufficiency in del(5q) MDS contributes to malignant transformation of hematopoietic stem cells. We asked how compound haploinsufficiency for Csnk1a1 and Egr1 in the common deleted region on chromosome 5 affects hematopoietic stem cells. Additionally, Trp53 was disrupted as the most frequently co-mutated gene in del(5q) MDS using CRISPR/Cas9 editing in hematopoietic progenitors of WT, Csnk1a1-/+, Egr1-/+, Csnk1a1/Egr1-/+ mice. A transplantable acute leukemia only developed in the Csnk1a1-/+ Trp53 edited recipient. Isolated blasts were indefinitely cultured ex vivo and gave rise to leukemia after transplantation, providing a tool to study disease mechanisms or to perform drug screenings. In a small-scale drug screening, the collaborative effect of Csnk1a1 haploinsufficiency and Trp53 sensitized blasts to the CSNK1 inhibitor A51 relative to WT or Csnk1a1 haploinsufficient cells. In vivo, A51 treatment significantly reduced blast counts in Csnk1a1 haploinsufficient/Trp53 acute leukemias and restored hematopoiesis in the bone marrow. Transcriptomics on blasts and their normal counterparts showed that the derived leukemia was driven by MAPK and Myc upregulation downstream of Csnk1a1 haploinsufficiency cooperating with a downregulated p53 axis. A collaborative effect of Csnk1a1 haploinsufficiency and p53 loss on MAPK and Myc upregulation was confirmed on the protein level. Downregulation of Myc protein expression correlated with efficient elimination of blasts in A51 treatment. The "myc signature" closely resembled the transcriptional profile of del(5q) MDS patients with TP53 mutation.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008926
  5. Leuk Res. 2023 Dec 19. pii: S0145-2126(23)00698-7. [Epub ahead of print]136 107433
    The clinical, molecular, and prognostic features of the 2022 WHO and ICC classification systems for myelodysplastic neoplasms.
    Vishesh Khanna, Rong Lu, Jyoti Kumar, Alfonso Molina, Henning Stehr, Elizabeth Spiteri, Michael Spinner, Oscar Silva, Sebastian Fernandez-Pol, Brent Tan, Peter L Greenberg.
      Myelodysplastic neoplasms (MDS) are clonal disorders of bone marrow failure exhibiting a variable risk of progression to acute myeloid leukemia. MDS exhibit certain prognostic genetic or cytogenetic abnormalities, an observation that has led to both the pathologic reclassification of MDS in the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) systems, as well as to an updated prognostic schema, the Molecular International Prognostic Scoring System (IPSS-M). This single-institution study characterized the molecular patterns and clinical outcomes associated with the 2022 WHO and ICC classification schemas to assess their clinical utility. Strikingly, with the exception of one individual, all 210 patients in our cohort were classified into analogous categories by the two pathologic/diagnostic schemas. Most patients (70%) were classified morphologically while the remaining 30% had genetically classified disease by both criteria. Prognostic risk, as assessed by the IPSS-M score was highest in patients with MDS with biallelic/multi-hit TP53 mutations and lowest in pts with MDS-SF3B1. Median leukemia-free survival (LFS) was shortest for those with MDS with biallelic/multi-hit TP53 (0.7 years) and longest for those with MDS with low blasts (LFS not reached). These data demonstrate the clear ability of the 2022 WHO and ICC classifications to organize MDS patients into distinct prognostic risk groups and further show that both classification systems share more similarities than differences. Incorporation of the IPSS-M and IPSS-R features provide additive prognostic and survival components to both the WHO and ICC classifications, which together enhance their utility for evaluating and treating MDS patients.
    Keywords:  ICC; IPSS-M; Myelodysplastic neoplasms; Myelodysplastic syndrome; WHO
    DOI:  https://doi.org/10.1016/j.leukres.2023.107433
  6. Leukemia. 2023 Dec 27.
    Distinct clinico-molecular arterial and venous thrombosis scores for myeloproliferative neoplasms risk stratification.
    Hélène Pasquer, Rafael Daltro de Oliveira, Loic Vasseur, Juliette Soret-Dulphy, Nabih Maslah, Lin-Pierre Zhao, Clémence Marcault, Marine Cazaux, Nicolas Gauthier, Emmanuelle Verger, Nathalie Parquet, William Vainchenker, Emmanuel Raffoux, Valérie Ugo, Damien Luque Paz, Lydia Roy, Wayne-Corentin Lambert, Jean-Christophe Ianotto, Eric Lippert, Stéphane Giraudier, Bruno Cassinat, Jean-Jacques Kiladjian, Lina Benajiba.
      Current recommended risk scores to predict thrombotic events associated with myeloproliferative neoplasms (MPN) do not discriminate between arterial and venous thrombosis despite their different physiopathology. To define novel stratification systems, we delineated a comprehensive landscape of MPN associated thrombosis across a large long-term follow-up MPN cohort. Prior arterial thrombosis, age >60 years, cardiovascular risk factors and presence of TET2 or DNMT3A mutations were independently associated with arterial thrombosis in multivariable analysis. ARTS, an ARterial Thrombosis Score, based on these four factors, defined low- (0.37% patients-year) and high-risk (1.19% patients-year) patients. ARTS performance was superior to the two-tiered conventional risk stratification in our training cohort, across all MPN subtypes, as well as in two external validation cohorts. Prior venous thrombosis and presence of a JAK2V617F mutation with a variant allelic frequency ≥50% were independently associated with venous thrombosis. The discrimination potential of VETS, a VEnous Thrombosis Score based on these two factors, was poor, similar to the two-tiered conventional risk stratification. Our study pinpoints arterial and venous thrombosis clinico-molecular differences and proposes an arterial risk score for more accurate patients' stratification. Further improvement of venous risk scores, accounting for additional factors and considering venous thrombosis as a heterogeneous entity is warranted.
    DOI:  https://doi.org/10.1038/s41375-023-02114-5
  7. Blood. 2023 Dec 28. 142(26): 2332
    CBFB::MYH11 fusion in a nonmonocytic acute myeloid leukemia.
    Julie Quessada, Marie Loosveld.
      
    DOI:  https://doi.org/10.1182/blood.2023022090
  8. Blood. 2023 Dec 28. pii: blood.2023021752. [Epub ahead of print]
    Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.
    Lorenz Bastian, Thomas Beder, Malwine Jeanette Barz, Sonja Bendig, Lorenz Bartsch, Wencke Walter, Nadine Wolgast, Björn Brändl, Christian Rohrandt, Björn-Thore Hansen, Alina M Hartmann, Katharina Iben, Dennis Das Gupta, Miriam Denker, Johannes Zimmermann, Michael Wittig, Guranda Chitadze, Martin Neumann, Folker Schneller, Walter Fiedler, Björn Steffen, Matthias Stelljes, Christoph Faul, Stefan Schwartz, Franz-Josef Müller, Gunnar Cario, Lana Harder, Claudia Haferlach, Heike Pfeifer, Nicola Gökbuget, Monika Brüggemann, Claudia D Baldus.
      Distinct diagnostic entities within BCR::ABL1-positive ALL are currently defined (ICC): 'lymphoid-only', with BCR::ABL1 observed exclusively in lymphatic precursors versus 'multilineage', where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of n=327 BCR::ABL1-positive ALL patients (age: 2 years - 84 years, median: 46) and identified two main gene expression clusters reproducible across four independent patient cohorts. FISH analysis of FACS-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n=18/18 vs n=3/16 patients, p<0.001), indicating that a 'multilineage' or 'lymphoid' BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A / PAX5 deletions / hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current GMALL protocols resulted in comparable disease-free survival (DFS) for 'multilineage' vs. 'lymphoid' cluster patients (3-year DFS: 70% vs 61%, p=0.530; n=91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.
    DOI:  https://doi.org/10.1182/blood.2023021752
  9. Blood. 2023 Dec 24. pii: blood.2023020515. [Epub ahead of print]
    TNF alpha promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.
    Georg Greiner, Nadine Witzeneder, Klara Klein, Simone Tangermann, Petra Kodajova, Eva Jaeger, Franz Ratzinger, Marlene C Gerner, Mohamad Jawhar, Sigrid Baumgartner, Karin Fruehwirth, Klaus G Schmetterer, Johannes Zuber, Karoline V Gleixner, Matthias Mayerhofer, Ilse Schwarzinger, Ingrid Simonitsch-Klupp, Harald Esterbauer, Constance Baer, Wencke Walter, Manja Meggendorfer, Robert Strassl, Torsten Haferlach, Karin Hartmann, Lukas Kenner, Wolfgang R Sperr, Andreas Reiter, Veronika Sexl, Michel Arock, Peter Valent, Gregor Hoermann.
      Systemic mastocytosis (SM) is defined by expansion and accumulation of neoplastic mast cells (MC) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor independent KIT activation and accumulation of MC. Tumor necrosis factor-alpha (TNF) is a pro-apoptotic and inflammatory cytokine that has been implicated in clonal selection of neoplastic cells. We found that KIT D816V increases expression and secretion of TNF. TNF expression in neoplastic MC is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation of human BM cells while KIT D816V+ cells are less susceptible to the cytokine potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of SM patients. TNF serum levels are significantly elevated in SM patients and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.
    DOI:  https://doi.org/10.1182/blood.2023020515
  10. Haematologica. 2023 Dec 28.
    TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.
    Haley E Ramsey, Agnieszka E Gorska, Brianna N Smith, Andrew J Monteith, Londa Fuller, Maria P Arrate, Michael R Savona.
      CD47-SIRPa is a myeloid check point pathway that inhibits phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in Acute Myeloid Leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high-affinity for CD47. Composed of the N-terminal D1 domain of SIRPα genetically linked to an inactive Fc domain from human IgG, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VEN based regimen can be augmented through CD47 inhibition (CD47i) in AML. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN+AZA regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that in cases of high medullary tumor burden, loss of resident macrophages reduced ALX efficiency. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via Poly(I:C), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of Poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.
    DOI:  https://doi.org/10.3324/haematol.2023.283850
  11. Cancer Med. 2023 Dec 26.
    Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
    Liqing Yang, Xiaoyu Wei, Yuping Gong.
       OBJECTIVE: The objective of the study was to determine the prognosis and risk factors for additional sex combs like 1 (ASXL1) mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
    POPULATION AND METHODS: This retrospective study enrolled 219 adult patients with newly diagnosed AML and MDS, who were treated in West China Hospital from October 2018 to January 2022. The primary clinical outcome was evaluated by overall survival (OS) followed up to January 2023. Kaplan-Meier analysis and Cox multivariate regression analysis were performed to identify potential prognostic parameters in patients with ASXL1 mutations (mt).
    RESULTS: A total of 34 (15.53%) ASXL1mt were detected, which occurred more frequently in the elderly and MDS cohorts (p < 0.001). Significantly lower blasts% (p < 0.001) and higher frequencies of mutant RUNX1, SRSF2, STAG2, EZH2, and SETBP1 (p < 0.02) were observed in the ASXL1mt cohort. Patients with ASXL1mt manifested with a worse complete remission rate (p = 0.011), and an inferior OS was shown in subgroups with MDS, co-mutations of RUNX1, SRSF2, or NRAS, as well as mutations in G646W (p < 0.05). Multivariate analysis considering age, diagnosis, co-mutations, and mutation site confirmed an independently adverse prognosis of mutations in G646W (HR = 4.302, 95% CI: 1.150-16.097) or RUNX1 co-mutations (HR = 4.620, 95% CI: 1.385-15.414) in the ASXL1mt cohort.
    CONCLUSION: Our study indicated that mutations in G646W or RUNX1 co-mutations are closely associated with a dismal clinical outcome in patients with AML and MDS harboring ASXL1mt . Considering the poor prognosis and risk factors in patients with ASXL1mt , more available treatments should be pursued.
    Keywords:  acute myeloid leukemia; additional sex combs like 1 (ASXL1); myelodysplastic syndrome; prognosis; risk factor
    DOI:  https://doi.org/10.1002/cam4.6871
  12. Blood. 2023 Dec 24. pii: blood.2023022260. [Epub ahead of print]
    Jak2V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross-talk.
    Wenli Liu, Joachim Pircher, Art Schuermans, Qurrat Ul Ain, Zhe Zhang, Michael C Honigberg, Mustafa Yalcinkaya, Tetsushi Nakao, Ashley Pournamadri, Tong Xiao, Mohammad Ali Hajebrahimi, Lisa Wasner, David Stegner, Tobias Petzold, Pradeep Natarajan, Steffen Massberg, Alan R Tall, Christian Schulz, Nan Wang.
      JAK2V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of three large cohort studies confirmed the association of JAK2VF with CVD, and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing pro-thrombogenic reticulated platelet counts. Gp1ba-Cre mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild type (WT) platelets showed increased activation, suggesting cross-talk between mutant and WT platelets. Jak2VF platelets showed 2 to 3-fold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared to controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross-talk to WT platelets, and suggests a potential beneficial effect of aspirin in JAK2VF CH.
    DOI:  https://doi.org/10.1182/blood.2023022260
  13. Blood Cell Ther. 2023 Nov 25. 6(4): 151-157
    Recent advances in ex vivo expansion of human hematopoietic stem cells.
    Masatoshi Sakurai.
      Hematopoietic stem cells (HSCs) are a rare cell population present in the bone marrow. They possess self-renewal and multipotent differentiation capacities and play a crucial role in lifelong hematopoiesis and reconstitution of the hematopoietic system after hematopoietic stem cell transplantation (HSCT). HSCT remains the only curative treatment for refractory hematologic disorders. Umbilical cord blood (CB) has several advantages as an alternative donor for HSCT, including HLA flexibility and lack of donor burden. However, CB has limitations in terms of cell dose, restricted donor options, and prolonged time to engraftment. Development of techniques for expanding HSCs ex vivo, especially those contained in CB, has become a goal in the field of hematology. Attempts have been made to use various combinations of cytokines for this purpose, but these protocols showed limited expansion rates and did not progress to clinical applications. Recent advances that include the addition of small molecules to cytokines have enabled long-term and stable ex vivo expansion of human HSCs. Clinical trials have been conducted with HSCs expanded in CB using these techniques, confirming their efficacy and safety. Furthermore, we recently developed a recombinant cytokine-free, albumin-free culture system for long-term expansion of human HSCs. This approach has the potential to selectively expand human HSCs more effectively than the previous protocols. We herein present an overview of ex vivo culture protocols for expanding human HSCs together with the results of clinical trials that utilized these techniques.
    Keywords:  chemicals; clinical trials; ex vivo; expansion; human hematopoietic stem cell; polymers
    DOI:  https://doi.org/10.31547/bct-2023-026
  14. Elife. 2023 Dec 28. pii: e83103. [Epub ahead of print]12
    Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice.
    Wenbin An, Maria Feola, Maayan Levy, Srinivas Aluri, Marc Ruiz-Martinez, Ashwin Sridharan, Eitan Fibach, Xiaofan Zhu, Amit Verma, Yelena Ginzburg.
      Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Ncoa4 and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.
    Keywords:  deferiprone; ineffective erythropoiesis; iron trafficking; medicine; mouse; myelodysplastic dyndrome; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.83103
  15. Leukemia. 2023 Dec 28.
    In vitro evidence of synergistic efficacy with asciminib combined with reduced dose of ATP-binding pocket tyrosine kinase inhibitors according to the ABL1 kinase domain mutation profile.
    Ho-Jae Han, Jaeyoon John Kim, Danielle Pyne, Anthea Travas, Amirthagowri Ambalavanan, Shinya Kimura, Michael W Deininger, Jong-Won Kim, Dennis Dong Hwan Kim.
      
    DOI:  https://doi.org/10.1038/s41375-023-02122-5
  16. Haematologica. 2023 Dec 28.
    LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia.
    Astrid Wintering, Anna Hecht, Julia Meyer, Eric B Wong, Juwita Hübner, Sydney Abelson, Kira Feldman, Vanessa E Kennedy, Cheryl A C Peretz, Deborah L French, Jean Ann Maguire, Chintan Jobaliya, Marta Rojas Vasquez, Sunil Desai, Robin Dulman, Eneida Nemecek, Hilary Haines, Mahmoud Hammad, Alaa El Haddad, Scott C Kogan, Zied Abdullaev, Farid F Chehab, Sarah K Tasian, Catherine C Smith, Mignon L Loh, Elliot Stieglitz.
      Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
    DOI:  https://doi.org/10.3324/haematol.2023.283776
  17. Exp Hematol. 2023 Dec 25. pii: S0301-472X(23)01807-6. [Epub ahead of print] 104148
    Nucleic Acid-Induced Inflammation on Hematopoietic Stem Cells.
    Giang To Vu, Valerie Awad, Maria Feliz Norberto, Teresa V Bowman, Eirini Trompouki.
      Hematopoiesis, the process of generating blood cells, starts during development with the primitive, pro-definitive and definitive hematopoietic waves. The first two waves will generate erythrocytes and myeloid cells while the definitive wave will give rise to hematopoietic stem cells (HSCs) that are multipotent and can produce most of the blood cells in an adult. While HSCs are highly proliferative during development, during adulthood they remain quiescent in the bone marrow. Inflammatory signaling in the form of interferons, interleukins, tumor necrosis factors and others are well established to influence both developmental and adult hematopoiesis. Here we discuss the role of specific inflammatory pathways that are induced by sensing nucleic acids. We discuss the role of RNA sensing members of the Toll-like, Rig-I-like, NOD-like, AIM2-like, protein kinase receptors and the DNA sensors Toll-like receptor, DDX41 and cGAS. The main downstream pathways of these receptors are discussed as well as their influence on developmental and adult hematopoiesis including hematopoietic pathologies.
    Keywords:  Hematopoiesis; inflammation; innate immunity; nucleic acid sensors
    DOI:  https://doi.org/10.1016/j.exphem.2023.104148
  18. Blood. 2023 Dec 28. 142(26): 2225-2226
    Toward an anatomy of human hematopoiesis.
    Oscar Brück.
      
    DOI:  https://doi.org/10.1182/blood.2023022740
  19. Lancet Haematol. 2023 Dec 21. pii: S2352-3026(23)00344-7. [Epub ahead of print]
    Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
    Domenico Russo, Michael Schmitt, Sylvain Pilorge, Matthias Stelljes, Toshiro Kawakita, Valerie L Teal, Barbara Haber, Charlene Bopp, Sanjeet S Dadwal, Cyrus Badshah.
       BACKGROUND: In a pivotal phase 3 trial of cytomegalovirus prophylaxis with letermovir for up to 100 days after allogeneic haematopoietic stem-cell transplantation (HSCT), 12% of participants developed clinically significant cytomegalovirus infection after letermovir was discontinued. We aimed to evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant cytomegalovirus infection from 100 days to 200 days following HSCT.
    METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 32 sites in six countries (France, Germany, Italy, Japan, the UK, and the USA). Cytomegalovirus‑seropositive HSCT recipients (aged ≥18 years) who had received letermovir prophylaxis for up to 100 days following HSCT and who remained at high risk of late clinically significant cytomegalovirus infection (with no previous history of clinically significant cytomegalovirus infection, defined as initiation of pre-emptive therapy for documented cytomegalovirus viraemia, onset of cytomegalovirus end-organ disease, or both) were eligible. Participants were randomly assigned (2:1) to receive either an additional 100 days (ie, a total of 200 days; letermovir group) of oral or intravenous letermovir 480 mg once daily, adjusted to 240 mg once daily for participants on cyclosporin A, or 100 days of a placebo comparator for letermovir (ie, a total of 100 days of letermovir; placebo group), following HSCT. Randomisation was done using a central interactive response technology system, stratified by study centre and haploidentical donor (yes or no). Participants, investigators, and sponsor personnel were masked to the treatment allocation. The primary efficacy endpoint was the proportion of participants from randomisation to week 28 (200 days after HSCT) with clinically significant cytomegalovirus infection, analysed using the full analysis set population (ie, those who received at least one dose of study intervention). Safety was analysed in all participants as treated (ie, those who received at least one dose according to the study intervention they were assigned to). This study is registered with ClinicalTrials.gov, NCT03930615, and is complete.
    FINDINGS: Between June 21, 2019, and March 16, 2022, 255 patients were screened for eligibility and 220 (86%) were randomly assigned (145 [66%] in the letermovir group and 75 [34%] in the placebo group). Between randomisation and week 28, four (3%) of 144 participants in the letermovir group and 14 (19%) of 74 in the placebo group developed clinically significant cytomegalovirus infection (treatment difference -16·1% [95% CI -25·8 to -6·5]; p=0·0005). The most common adverse events among participants in the letermovir group versus the placebo group were graft-versus-host disease (43 [30%] vs 23 [31%]), diarrhoea (17 [12%] vs nine [12%]), nausea (16 [11%] vs 13 [18%]), pyrexia (13 [9%] vs nine [12%]), and decreased appetite (six [4%] vs nine [12%]). The most frequently reported serious adverse events were recurrent acute myeloid leukaemia (six [4%] vs none) and pneumonia (three [2%] vs two [3%]). No deaths were considered to be drug-related by the investigator.
    INTERPRETATION: Extending the duration of letermovir prophylaxis to 200 days following HSCT is efficacious and safe in reducing the incidence of late clinically significant cytomegalovirus infection in patients at risk.
    FUNDING: Merck Sharp & Dohme LLC.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00344-7
  20. Blood Cell Ther. 2023 Aug 25. 6(3): 77-79
    Gilteritinib in peritransplant period for relapsed or refractory FLT3-mutated acute myeloid leukemia: A case report of three patients.
    Fuka Mima, Shigeo Fuji, Kumi Shibata, Shuhei Kida, Kazuhito Tsutsumi, Yuma Tada, Yasuhiro Shingai, Sayako Yuda, Takafumi Yokota, Jun Ishikawa.
      Patients with relapsed or refractory acute myeloid leukemia (RR-AML) with mutations of FMS-like tyrosine kinase 3 (FLT3) have a poor prognosis even after allogeneic hematopoietic cell transplantation (allo-HCT). Multiple FLT3 inhibitors, including gilteritinib, have been developed and serve as treatment options for RR-AML. Here, we describe three cases of FLT3 mutated RR-AML that were successfully treated with gilteritinib administration before and after allo-HCT. Gilteritinib treatment before HCT was helpful in achieving remission. However, HCT often resulted in mild liver damage, and careful introduction of gilteritinib after HCT at a lower dose may be helpful for its safe usage. The three cases discussed had a successful clinical outcome in terms of disease control as well as the management of side effects associated with gilteritinib treatment.
    Keywords:  FLT3; acute myeloid leukemia; allogeneic hematopoietic cell transplantation; gilteritinib
    DOI:  https://doi.org/10.31547/bct-2023-003
  21. Br J Haematol. 2023 Dec 26.
    How to improve treatment-free remission eligibility in chronic myeloid leukaemia?
    Alessandro Costa, Massimo Breccia.
      The achievement of treatment-free remission (TFR) has become a significant clinical end-point in the management of patients with chronic myeloid leukaemia (CML), providing an opportunity to discontinue therapy with tyrosine kinase inhibitors (TKIs) while maintaining deep molecular response (DMR). Early studies, such as the French STIM trial, have demonstrated that a portion of patients can maintain DMR after treatment cessation, with rates ranging from 40% to 50%, and most relapses occurring within the first 6 months. Key prognostic factors for successful TFR, including treatment duration, duration of DMR, risk scores, and transcript type, have been identified. Optimal patient selection for TFR remains a challenge, but recent research provides insights into potential strategies to increase TFR eligibility. Evidence suggests that early intervention switching to achieve optimal response, treatment combinations, proactive switch in the case of absence of DMR, dose-optimization and induction-maintenance approach can improve molecular responses and, consequently, enhance TFR eligibility. In this review, we report and discuss all the potential therapeutic strategies that may enhance eligibility for a first attempt at TFR, with a particular emphasis on potential future approaches.
    Keywords:  chronic myeloid leukaemia; combination; dose-optimization; eligibility; induction-maintenance; novel agents; proactive; switch; treatment-free remission
    DOI:  https://doi.org/10.1111/bjh.19269
  22. Blood. 2023 Dec 24. pii: blood.2023020232. [Epub ahead of print]
    Association between elevated white blood cell counts and thrombotic events in polycythemia vera: Analysis from REVEAL.
    Aaron T Gerds, Ruben A Mesa, John M Burke, Michael R Grunwald, Brady L Stein, Peg Squier, Jingbo Yu, J E Hamer-Maansson, Stephen T Oh.
      Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells, and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Whereas an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The pRospective obsErvational study of patients with polycythemia VEra in US clinicAL practices (REVEAL) collected prospective clinical data from 2510 patients with PV with a median (range) follow up of 44.7 (2-59) months from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates) and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit >45% (hazard ratio (HR) = 1.84; [95% confidence interval, 1.234-2.749], P = .0028) and WBC >11×109/L (HR = 2.35 [1.598-3.465], P < .0001) . Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC >12×109/L was significantly associated with TE occurrence (HR = 1.95 [1.066-3.554], P = .0300). The results support incorporation of WBC count into PV risk-stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial is registered at www.clinicaltrials.gov as #NCT02252159.
    DOI:  https://doi.org/10.1182/blood.2023020232
  23. Thromb Res. 2023 Dec 22. pii: S0049-3848(23)00360-2. [Epub ahead of print]234 32-35
    Decreased patency of transjugular intrahepatic portosystemic shunts performed for splanchnic vein thrombosis in patients with myeloproliferative neoplasms.
    Margaret Shyu, Adam Winters, Leonard Naymagon, Rahul Patel, Thomas D Schiano, Douglas Tremblay.
      
    Keywords:  Essential thrombocythemia; Myeloproliferative neoplasm; Polycythemia vera; Portal hypertension; Splanchnic vein thrombosis; Transjugular intrahepatic portosystemic shunt
    DOI:  https://doi.org/10.1016/j.thromres.2023.12.013
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