bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–12–22
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London



  1. Br J Haematol. 2024 Dec 19.
      Acute myeloid leukaemia (AML) arising from a myeloproliferative neoplasm (MPN) is more aggressive and less responsive to therapies compared to de novo AML. Olutasidenib, an oral small-molecule inhibitor of mutated IDH1 (mIDH1), showed encouraging and durable responses in a phase 1/2 study of adults with post-MPN mIDH1 AML. Patients received olutasidenib 150 mg BID monotherapy or in combination with azacitidine. Primary end-points: safety and best response defined as complete remission (CR), CR with partial haematological recovery or morphological leukaemia-free state (MLFS). Analysis included 15 patients with post-MPN mIDH1 AML; 10 had relapsed or refractory AML and five had newly diagnosed AML. Six were treated with olutasidenib monotherapy and nine in combination with azacitidine. Treatment emergent adverse events occurred in 15 patients, three of whom discontinued therapy. CR: 40% (n = 6/15); median duration of response: 15.6 months (range: 1.7-44.3); CR with incomplete haematological recovery: 13% (n = 2/15); MLFS: 7% (n = 1/15); composite complete remission (CRc): 53% (n = 8/15); and overall response rate (ORR): 60% (9/18). Median duration of CRc and ORR: 13.15 (range: 2.4-48.7) and 14.3 months (range: 2.4-48.7), respectively, and median overall survival: 13.8 months (95% confidence interval: 3.70-23.7). Olutasidenib demonstrated encouraging response rates with a manageable safety profile for patients with post-MPN mIDH1 AML.
    Keywords:  IDH1 mutation; acute myeloid leukaemia; blast‐phase myeloproliferative neoplasm; myeloproliferative neoplasms
    DOI:  https://doi.org/10.1111/bjh.19944
  2. Blood Adv. 2024 Dec 18. pii: bloodadvances.2024014698. [Epub ahead of print]
      Mutation of DNMT3A, encoding a de novo methyltransferase essential for cytosine methylation, is a common early event in clonal hematopoiesis (CH) and adult acute myeloid leukemia (AML). Spontaneous deamination of methylated cytosines damages DNA, which is repaired by the base excision repair (BER) enzymes MBD4 and TDG. Congenital MBD4-deficiency has been linked to early-onset CH and AML, and is marked by exceedingly high levels of DNA damage and mutation of DNMT3A. Strikingly, wildtype (WT) DNMT3A binds TDG, thereby potentiating its repair activity. Since TDG is the only remaining BER enzyme in MBD4-deficient AML patients capable of repairing methylation damage, we investigated whether mutant DNMT3A negatively affects the repair function of TDG. We found that, whereas WT DNMT3A stimulates TDG function, mutant DNMT3A impairs TDG-mediated repair of DNA damage in vitro. In light of this finding and to extrapolate our observations to the broader AML patient population, we investigate here the genetic profiles and survival outcomes of AML patients with single (SM) versus double mutant (DM) DNMT3A. DM DNMT3A AML patients show a characteristic driver mutation landscape and reduced overall survival when compared to SM DNMT3A AML patients. Importantly, whole-genome sequencing showed a trend for increased DNA damage in primary DM DNMT3A AML samples, especially when DNMT3A mutations are located at the DNMT3A-TDG interaction interface.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014698
  3. Bone Marrow Transplant. 2024 Dec 19.
      The treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300-400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140.
    DOI:  https://doi.org/10.1038/s41409-024-02499-6
  4. Leukemia. 2024 Dec 17.
      The nucleophosmin (NPM1) gene encodes for the most abundant nucleolar protein. Thanks to its property to act as histone chaperone and to shuttle between the nucleus and cytoplasm, the NPM1 protein is involved in multiple cellular function that are here extensively reviewed and include the formation of the nucleolus through liquid-liquid phase separation, regulation of ribosome biogenesis and transport, control of DNA repair and centrosome duplication as well as response to nucleolar stress. NPM1 is mutated in about 30-35% of adult acute myeloid leukemia (AML). Due to its unique biological and clinical features, NPM1-mutated AML is regarded as a distinct leukemia entity in the WHO 5th edition and ICC classifications of myeloid malignancies. The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML.
    DOI:  https://doi.org/10.1038/s41375-024-02476-4
  5. Haematologica. 2024 Dec 19.
      Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ- 75276617 (bleximenib) targets the menin-KMT2A interaction and provides preclinical efficacy in AML (Kwon et al1). Here, we provide mechanistic insight in how JNJ- 75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte macrophage progenitor (GMP)-like AMLs display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AMLs are sensitive, and some NPM1wt AML subtypes without KMT2A-MLLT3 rearrangements benefit from menin-KMT2A inhibition. Genome-wide ChIP-seq studies revealed patient-specific epigenetic alterations upon JNJ-75276617 treatment, uncovering a striking upregulation of MHC class I and class II expression as a consequence of epigenetic changes upon menin-KMT2A inhibition, independent of MEIS1 loss but involving CIITA activation. Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery.
    DOI:  https://doi.org/10.3324/haematol.2024.285616
  6. Br J Haematol. 2024 Dec 19.
      Acute myeloid leukaemia with NUP98 rearrangement (AML-NUP98) has been previously described in paediatric patients, and the clinical significance in adult AML patients remains largely unexplored. In this study, we identified specific partner fusion genes and examined somatic co-mutations and clonal evolution longitudinally in adult AML-NUP98 patients. Our comprehensive analysis provides an understanding of NUP98 rearrangement and co-mutations influencing clonal evolution and disease progression and offers valuable insights into potential therapeutic strategies. Further multiple centre studies are needed to investigate this entity in adult patients and improve treatment strategy.
    Keywords:  acute leukaemia; cytogenetics of leukaemia; molecular haematology; myeloid leukaemia; translocation
    DOI:  https://doi.org/10.1111/bjh.19962
  7. EJHaem. 2024 Dec;5(6): 1274-1277
      Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).
    Keywords:  FLT3 inhibitors; acute myeloid leukemia; gilteritinib; midostaurin; real‐world
    DOI:  https://doi.org/10.1002/jha2.1045
  8. Exp Hematol. 2024 Dec 12. pii: S0301-472X(24)00561-7. [Epub ahead of print] 104697
      Myeloid malignancies are a spectrum of clonal disorders driven by genetic alterations that cooperatively confer aberrant self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs). Induced pluripotent stem cells (iPSCs) can be differentiated into HSPCs and have been widely explored for modeling hematological disorders and cell therapies. More recently, iPSCs models have been applied to study the origins and pathophysiology of myeloid malignancies, motivated by the appreciation for the differences in human oncogene function and the need for genetically defined models that recapitulate leukemia development. In this review, we will provide a broad overview of the rationale, the challenges, practical aspects, history, and recent advances of iPSC models for modeling myeloid neoplasms. We will focus on the insights into the previously unknown aspects of human oncogene function and cooperativity gained through the use of these models. It is now safe to say that iPSC models are a mainstay of leukemia modeling "toolbox" alongside primary human cells from normal and patient sources.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104697
  9. Bone Marrow Transplant. 2024 Dec 18.
      Patients with AML and measurable residual disease (MRD) undergoing allogeneic hematopoietic cell transplantation (HCT) may benefit from myeloablative conditioning (MAC) when feasible to reduce relapse risk. Fludarabine-Melphalan (FluMel) is a common reduced intensity conditioning (RIC) regimen; however, data in MRD+ patients is sparse. We performed a retrospective review of AML patients who underwent their first HCT (2016-2021) without morphologic disease at City of Hope who had pre-transplant marrow evaluated for MRD using multicolor flow cytometry (MFC) and received radiation-based MAC or FluMel conditioning. We identified 312 patients; 44 with MRD+ disease pre-HCT. The 24-month overall survival (OS), leukemia-free survival (LFS) and cumulative incidence of relapse (CIR) were 47.7%, 40.9%, and 38.6% in MRD+, and 78.0%, 73.9%, and 14.6% in MRD- patients. Radiation-based MAC was given to 136 (43.5%) patients (n = 20 with MRD+) and FluMel was given to 174 (55.8%) patients (n = 24 with MRD+). In patients with MRD+, there was no statistically significant difference between those who received MAC vs. FluMel in 24-month OS (60% vs. 38%, p = 0.21), or CIR (35% vs. 42%, p = 0.59), respectively. Our data substantiates the adverse impact of MRD in patients with AML undergoing HCT; FluMel is a reasonable option for MRD+ patients unfit for MAC.
    DOI:  https://doi.org/10.1038/s41409-024-02491-0
  10. Discov Oncol. 2024 Dec 18. 15(1): 786
      Essential thrombocytosis (ET) is a chronic myeloproliferative neoplasm. There is a rare possibility of its transformation from ET into acute myeloid leukemia (AML). While the TP53 mutation is a well-known risk factor for AML, limited research exists regarding ET patients who develop AML with TP53 mutations. Among three ET transformed AML patients, two exhibited TP53 mutations, with an increased number of AML cells. Conversely, the third ET patient who transformed to AML without TP53 mutations had a lower burden of AML cells. The patients with TP53 mutations had shorter survival times compared to that without mutations, in response to decitabine treatment. In contrast, the patient with ET transformed AML without TP53 mutations showed a better response to decitabine. The ET transformed AML without TP53 mutations patient exhibited a survival period exceeding 20 months. ET patients who develop AML with a high allelic burden of TP53 mutations may experience a more aggressive disease progression and severe complications compared to AML patient without TP53 mutations. Our report sheds light on the distinct clinical presentations of ET patients who develop AML, characterized by different TP53 mutations and varying therapeutic outcomes when treated with decitabine. However, further studies that include a larger quantity of samples are needed to elucidate the precise underlying molecular mechanisms involved in this process.
    Keywords:  Acute myeloid leukemia; Essential thrombocytosis; Prognosis; Transformation
    DOI:  https://doi.org/10.1007/s12672-024-01665-y
  11. Blood. 2024 Dec 10. pii: blood.2024024505. [Epub ahead of print]
      Pediatric acute myeloid leukemia frequently harbor fusion oncogenes associated with poor prognosis, including KMT2A, NUP98 and GLIS2 rearrangements. While murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSC). IPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL) reflected by flow cytometry and single cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knock-out abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, characterization of a novel human iPSC-derived AMKL model revealed hijacking of the osteogenic homeobox transcription factor DLX3 as an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.
    DOI:  https://doi.org/10.1182/blood.2024024505
  12. Cancers (Basel). 2024 Nov 29. pii: 4017. [Epub ahead of print]16(23):
      KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A-menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge. This review explores combination therapies aimed at overcoming resistance and improving patient outcomes. Potential strategies include inhibiting DOT1L, a histone methyltransferase essential for KMT2A-driven transcription, and BRD4, a regulator of transcriptional super-enhancers. Additionally, targeting MYC, a key oncogene frequently upregulated in KMT2A-rearranged leukemia, offers another approach. Direct inhibition of KMT2A-fusion proteins and c-MYB, a transcription factor critical for leukemic stem cell maintenance, is also explored. By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.
    Keywords:  KMT2A-rearranged leukemia; acute myeloid leukemia; combination therapies; menin inhibitors; targeted therapies; therapeutic resistance
    DOI:  https://doi.org/10.3390/cancers16234017
  13. Blood Adv. 2024 Dec 10. pii: bloodadvances.2024013661. [Epub ahead of print]
      The Janus kinase 2 (JAK2) V617F mutation activates the transcription pathway and has been well-characterized as a driver of myeloproliferative neoplasms (MPNs). Recently, there has been a heightened interest in understanding germline predisposition to hematological malignancies including MPN, including several reports of familial MPN. Here, we retrospectively analyzed medical records and data from genetic testing to describe twelve patients with germline variants at amino acid position 564 of JAK2. This includes three supportive cases adding to prior literature regarding the germline JAK2 R564Q association with hereditary thrombocythemia, as well as confirmation of JAK2 R564L as a germline variant associated with MPN. Importantly, the symptomatic burden for many of the individuals in this series is comparable to that of individuals with the canonical V617F mutation profile. In the JAK2 R564Q cases, we noted a pattern of familial aggregation, presence of congenital thrombocythemia and co-occurrence with hematological neoplasms. Identification of germline predisposition is essential to understanding the pathogenesis of disease, impact on families, and opportunities for preventive care. Continued research is essential to further characterize the penetrance of these conditions, and how best to monitor, treat and optimize management for these families.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013661
  14. bioRxiv. 2024 Dec 03. pii: 2024.11.29.625909. [Epub ahead of print]
      Myeloid leukemias are heterogeneous cancers with a diverse mutational landscape. Though many mutated genes fall within common protein complexes, some lack known functional partners and have unclear roles. PHF6 is a poorly-understood chromatin-binding protein with recurrent mutations that confer an unfavorable prognosis in acute and chronic myeloid leukemias. Here, using human PHF6 knockout and rescue, we show that PHF6 is a transcriptional repressor that binds active chromatin and suppresses a stemness gene program. We dissect nine clinical missense mutations and show that all produce unstable, hypomorphic, or non-functional PHF6 protein. Guided by convergent lines of evidence, we identify PHIP, a newly recognized AML-mutated protein, as a functional partner of PHF6. We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert downstream transcriptional effects. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.
    DOI:  https://doi.org/10.1101/2024.11.29.625909
  15. J Clin Invest. 2024 Dec 16. pii: e173403. [Epub ahead of print]134(24):
      Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.
    Keywords:  Hematology; Hematopoietic stem cells; Leukemias
    DOI:  https://doi.org/10.1172/JCI173403
  16. Blood Adv. 2024 Dec 18. pii: bloodadvances.2024014999. [Epub ahead of print]
      The Acute Promyelocytic Leukemia Asian Consortium analyzed a contemporaneous cohort of newly-diagnosed APL patients treated with and without frontline arsenic trioxide (ATO) in six centers. The objectives were to define the impact of ATO on early deaths and relapses, and its optimal positioning in the overall treatment strategy. In a 21.5-year period, 324 males and 323 females at a median age of 45.5 (range: 18.1-91.8) years (low/intermediate risk, N=448; high-risk, N=199) were treated. Regimens included frontline all-trans retinoic acid (ATRA)/chemotherapy and maintenance with/without ATO (N=436); ATRA/intravenous-ATO/chemotherapy (ATRA/i.v.-ATO; N=61); and ATRA/oral-ATO/ascorbic acid with ATO maintenance (oral-AAA; N=150). The ATRA/chemotherapy group, compared with the ATO-containing (ATRA/i.v.-ATO and oral-AAA) groups, had significantly more frequent early deaths within 60 days (8.3% versus 3.3%; P=0.05); inferior 60-day survival (91.7% versus 98.4%/96%; P<0.001); inferior 5-year relapse-free survival (RFS) (76.9% versus 92.8%/97.8%; P<0.001) and inferior 5-year overall survival (OS) (84.6% versus 91.4%/92.3%; P=0.03). Addition of oral-ATO maintenance could partly mitigate the inferior 5-year RFS resulting from omission of ATO during induction (ATRA/chemotherapy/non-ATO maintenance versus ATRA/chemotherapy/ATO maintenance versus ATRA/i.v.-ATO versus oral-AAA: 71.1% versus 87.9% versus 92.8% versus 97.8%, P<0.001). The favorable survival impacts of ATO were observed in both low/intermediate-risk and high-risk patients, so that conventional risks (high leucocyte and low platelet counts) were overcome. Therefore, ATO decreased early deaths, improved 60-day survival, and resulted in significantly superior RFS and OS. Its benefits were most obvious in frontline treatment, but were still observed during maintenance. (ClinicalTrials.gov Identifier: NCT04251754).
    DOI:  https://doi.org/10.1182/bloodadvances.2024014999
  17. Blood Adv. 2024 Dec 18. pii: bloodadvances.2024013970. [Epub ahead of print]
      Pulmonary Hypertension (PH) is a known complication of myeloproliferative neoplasms (MPN) with estimated prevalence as high as 50%. Patients with Polycythemia Vera (PV) report a wide spectrum of symptoms that significantly overlap with those reported by patients with PH. Yet, it is not known how PH affects outcomes and survival in patients with PV. To address this gap, we investigated the impact of echocardiogram (ECHO) PH risk on survival of patients with PV from our large single center cohort. Of 637 patients with PV, 134 had at least one ECHO and were included for analysis. Overall survival (OS) did not differ between patients who had or did not have ECHO. PH risk was established based on tricuspid regurgitation jet velocity. Kaplan-Meier analysis showed that high PH risk is associated with shortened survival compared to mild PH risk (median survival 1.7 vs 3.7 years) or normal PH risk (median survival not yet reached). Cox Proportional Hazard Models found high PH risk was associated with >3-fold increased risk of death, independent of age and thrombosis history. Logistic regression identified age (odds ratio 6.9) and duration of PV diagnosis (odds ratio 5.4) as significant risks for PH. Based upon these results and receiver operator characteristic optimization, we recommend echocardiographic screening for patients with PV older than 70 years or with duration of PV longer than 8 years. Further studies inclusive of invasive hemodynamics, advanced CV imaging, and MPN-associated biomarkers are needed to best characterize this Group 5 PH patient population for therapeutic interventions.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013970
  18. N Engl J Med. 2024 Dec 19. pii: 10.1056/NEJMc2414034#sa3. [Epub ahead of print]391(24): 2388
      
    DOI:  https://doi.org/10.1056/NEJMc2414034
  19. Blood Cancer J. 2024 Dec 18. 14(1): 216
      To compare the efficacy and safety of gecacitinib (also known as jaktinib) with hydroxyurea (HU) in treating myelofibrosis (MF) patients. In this multicenter, randomized phase 3 trial (ZGJAK016), intermediate- or high-risk primarily JAK inhibitor naïve MF patients were assigned in a 2:1 ratio to receive either gecacitinib (100 mg twice a day, BID) or HU (500 mg BID). The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) from baseline at week 24. Secondary endpoints included the best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile. At 24 weeks, the SVR35 was reached by 64.8% of patients on gecacitinib (46/71), compared to 26.5% on HU (9/34), P = 0.0002. The best spleen response rates were also superior for gecacitinib at 81.7%, vs 32.4% for HU, P < 0.0001. The TSS50 rates were 62.0% for gecacitinib- and 50% for HU-treated patients. Among non-transfusion-dependent patients with baseline hemoglobin (HGB) ≤ 100 g/L, 31.0% (13/42) in the gecacitinib group showed a ≥20 g/L increase in HGB, compared to 15.0% (3/20) in HU group. The common grade ≥ 3 treatment-emergent adverse events (TEAEs), including anemia (26.8% vs 44.1%), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%), were less frequent with gecacitinib than HU. Treatment discontinuation due to TEAEs was lower in gecacitinib (7.0%) compared to HU (11.8%). Gecacitinib demonstrates superior efficacy and a more favorable safety profile compared to HU, making it a promising treatment option for managing MF, particularly in patients with anemia (This trial was registered with ClinicalTrials.gov, (NCT04617028)).
    DOI:  https://doi.org/10.1038/s41408-024-01202-8
  20. Cell. 2024 Dec 12. pii: S0092-8674(24)01324-2. [Epub ahead of print]
      Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m5C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N6-methyladenosine (m6A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.
    Keywords:  ATP production; B cell malignancies; CAR-T; CD19; MHC-II; YTHDF2; m(5)C; m(6)A; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2024.11.007
  21. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02590-0. [Epub ahead of print] 108088
      While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using 1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domain-dependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.
    Keywords:  NMR; SH2 domain; SH3 domain; Src-family kinase; hydrogen-deuterium exchange mass spectrometry; kinase inhibitors; tyrosine kinases
    DOI:  https://doi.org/10.1016/j.jbc.2024.108088
  22. J Hematol Oncol. 2024 Dec 18. 17(1): 125
       BACKGROUND: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib.
    METHODS: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily.
    RESULTS: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile.
    CONCLUSIONS: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice.
    TRIAL REGISTRATION: NCT03578367.
    Keywords:  ASC4MORE; Add-on; Asciminib; CML; Combination; Deep molecular response; Imatinib; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1186/s13045-024-01642-6
  23. Nature. 2024 Dec 18.
      Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.
    DOI:  https://doi.org/10.1038/s41586-024-08318-8