bims-hemali Biomed News
on Hematologic malignancies
Issue of 2026–01–04
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Targeting STK17B: unlocking ferroptosis in myeloma.
  2. Brentuximab Vedotin and Nivolumab in Combination With Chemotherapy for Nonbulky, Early-Stage Classical Hodgkin Lymphoma.
  3. Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)(CCND1;IGH).
  4. Early BCR::ABL1 Reduction as a Predictor of Deep Molecular Response in Pediatric Chronic-Phase Chronic Myeloid Leukemia.
  5. Bone Marrow Edema and Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia.
  6. How blasts get into the skin-and how to get rid of them.
  7. Extramedullary Disease-Achilles Heel in Myeloma?
  8. Mixed phenotype acute leukemia, the dissection of an enigmatic disease in the era of novel therapies.
  9. Rapid Hematological and Molecular Response to Pegylated Interferon in WHO-Defined Pre-Fibrotic Myelofibrosis.
  10. CELMoD-antibody conjugates unlock a CD38 feedback loop in multiple myeloma.
  11. Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability.
  12. Parenteral replacement therapy with iron dextran or ferumoxytol in patients with iron deficiency.
  13. Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity.
  14. Polymeric Lysosome-Targeting Chimeras (PolyTACs): Extracellular Targeted Protein Degradation without Co-Opting Lysosome-Targeting Receptors.
  15. Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies.
  16. How to Read a Next-Generation Sequencing Report for AML and MDS? What Hematologists Need to Know.
  1. Blood. 2026 Jan 01. 147(1): 6-7
    Targeting STK17B: unlocking ferroptosis in myeloma.
    Bei Liu.
      
    DOI:  https://doi.org/10.1182/blood.2025031316
  2. Blood. 2025 Dec 29. pii: blood.2025030190. [Epub ahead of print]
    Brentuximab Vedotin and Nivolumab in Combination With Chemotherapy for Nonbulky, Early-Stage Classical Hodgkin Lymphoma.
    Jeremy S Abramson, David J Straus, Nancy L Bartlett, John M Burke, Ryan C Lynch, Eva Domingo-Domenech, Brian T Hess, Steven R Schuster, Yuliiya Linhares, Mitul D Gandhi, Harsh R Shah, Wojciech Jurczak, Alessandro Re, Uwe Hahn, H Miles Prince, Wenchuan Guo, Griffith Davis, Linda Ho, Michelle Fanale, Christopher A Yasenchak, Hun Ju Ju Lee.
      Most patients with early-stage classical Hodgkin lymphoma (cHL) are treated with doxorubicin, bleomycin, vinblastine, and dacarbazine with or without radiation therapy, although studies are now evaluating the incorporation of novel agents paired with abbreviated chemotherapy. We present the efficacy and safety of brentuximab vedotin (BV) and nivolumab in combination with doxorubicin and dacarbazine (AN+AD) in patients with early-stage cHL. In this phase 2 study, patients with non-bulky (<10 cm) Ann Arbor stage I or II cHL received 4 cycles of AN+AD. The primary endpoint was complete response (CR) rate at end of treatment (EOT) by investigator. At the time of this analysis, 154 patients received ≥1 dose of AN+AD. The objective response rate at EOT was 96% (95% CI, 91.7-98.6), and the CR rate was 92% (95% CI, 86.0-95.4). In the favorable (n=56) and unfavorable (n=97) subgroups, CR rates were 95% (95% CI, 85.1-98.9) and 91% (95% CI, 83.1-95.7), respectively. The proportion of patients with duration of CR of at least 2 years was 96% (95% CI, 90.9-98.4). At a median follow-up of 27.9 months, the estimated 2-year PFS rate was 97% (95% CI, 92.0-98.8). Any-grade and grade ≥3 treatment-emergent adverse events occurred in 99% and 44% of patients, respectively; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events occurred in 22% of patients. One disease-related death was reported after the safety reporting period. Results from this study support the use of BV and nivolumab in combination with limited chemotherapy in patients with non-bulky, early-stage cHL. ClinicalTrials.gov: NCT03646123.
    DOI:  https://doi.org/10.1182/blood.2025030190
  3. Blood. 2026 Jan 02. pii: blood.2025029996. [Epub ahead of print]
    Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)(CCND1;IGH).
    Marcella Kaddoura, Julia Erin Wiedmeier-Nutor, Vikas A Gupta, Tomas Jelinek, Bachisio Ziccheddu, Suganti Shivaram, Hongwei Tang, Rebecca W Owens, Tereza Ševčíková, Rodrigo Fonseca, Michael A Durante, Benjamin T Diamond, Logan Zhao, Yuan Xiao Zhu, Chang-Xin Shi, Shannon M Matulis, Constantine S Mitsiades, Carl Ola Landgren, Saad Z Usmani, Roman Hajek, Marta Chesi, P Leif Bergsagel, Esteban Braggio, Lawrence H Boise, Rafael Fonseca, Shaji K Kumar, Francesco Maura, Linda B Baughn.
      Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. Not all t(11;14)(CCND1;IGH) patients respond to treatment and some progress early after initial response. To investigate this, we interrogated 44 whole genome and exome sequencing data from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 MM patients. Presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired, pre- and post-venetoclax treatment samples, post-venetoclax progression was recurrently driven by the selection of genomic events in BCL2/MCL1 and RAS pathways and of high-risk features (e.g., loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.
    DOI:  https://doi.org/10.1182/blood.2025029996
  4. Cancers (Basel). 2025 Dec 15. pii: 3994. [Epub ahead of print]17(24):
    Early BCR::ABL1 Reduction as a Predictor of Deep Molecular Response in Pediatric Chronic-Phase Chronic Myeloid Leukemia.
    Xingchen Wang, Wenbin An, Chenmeng Liu, Bang Zhang, Yunlong Chen, Yang Wan, Xiaolan Li, Lipeng Liu, Fang Liu, Li Zhang, Yao Zou, Xiaojuan Chen, Yumei Chen, Ye Guo, Tianyuan Hu, Yingchi Zhang, Xiaofan Zhu, Wenyu Yang.
      Background: Tyrosine kinase inhibitors (TKIs) have transformed the prognosis of chronic myeloid leukemia (CML), but pediatric patients face unique challenges due to prolonged exposure. Early molecular response (EMR, BCR::ABL1 ≤ 10% at 3 months) is a recognized predictor of favorable outcomes in adults and has been correlated with improved responses in children. However, its relationship with achieving deep molecular remission (DMR, BCR::ABL1 ≤ 0.01%) in pediatric CML remains unclear. Methods: We performed a single-center, retrospective analysis of 103 pediatric patients with chronic-phase CML treated with frontline TKIs. Among them, 88 were evaluable for molecular response. BCR::ABL1 transcript levels were quantified by real-time quantitative PCR on the International Scale, and molecular responses were assessed. Associations between early molecular dynamics and long-term outcomes were evaluated using Kaplan-Meier and cumulative incidence analyses. Results: At 3 months, 64.8% achieved EMR. Early responders had significantly higher MMR rates at 12 months (80.8% vs. 5.6%; p = 0.00018) and DMR at 24 months (70.4% vs. 42.2%; p = 0.029). The ≥0.45-log reduction in BCR::ABL1 transcripts at 3 months predicted shorter times to MMR (median 11 vs. 29 months) and DMR (18 vs. 50 months), as well as higher overall MMR (p = 0.011) and DMR (p = 0.014) incidences. Bone marrow fibrosis correlated with inferior molecular outcomes (p = 0.017 for MMR). Conclusions: Early BCR::ABL1 decline kinetics independently predict molecular depth in pediatric CML. Quantitative early transcript reduction may guide risk-adapted management and optimize long-term TKI strategies in children.
    Keywords:  BCR::ABL1; TKI; deep molecular remission; pediatric chronic myeloid leukemia
    DOI:  https://doi.org/10.3390/cancers17243994
  5. Diagnostics (Basel). 2025 Dec 08. pii: 3112. [Epub ahead of print]15(24):
    Bone Marrow Edema and Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia.
    Sabina Russo, Manlio Fazio, Giuseppe Mirabile, Raffaele Sciaccotta, Fabio Stagno, Alessandro Allegra.
      Background and Clinical Significance: Tyrosine kinase inhibitors (TKIs) have transformed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) into a largely manageable chronic disease. However, off-target toxicities are increasingly recognized; rarer complications such as bone marrow edema (BME) remain underreported. BME is a radiological syndrome characterized by excess intramedullary fluid on fat-suppressed T2/STIR magnetic resonance imaging sequences and may progress to irreversible osteochondral damage if unrecognized. We report a case series of TKI-associated BME and propose a practical diagnostic-therapeutic framework. Case Presentation: We describe three patients with Ph+ CML who developed acute, MRI-confirmed BME of the lower limb during TKI therapy. Case 1 developed unilateral then bilateral knee BME, temporally associated first with dasatinib and subsequently with imatinib; symptoms improved after TKI interruption, bisphosphonate therapy, and supportive measures, and did not recur after switching to bosutinib. Case 2 presented with proximal femoral BME during long-term imatinib; imatinib was stopped, intravenous neridronate administered, and bosutinib initiated with clinical recovery and later near-complete radiological resolution. Case 3 experienced multifocal foot and ankle BME during imatinib; symptoms resolved after drug discontinuation and bisphosphonate therapy, and disease control was re-established with bosutinib without recurrence of BME. All patients underwent molecular monitoring and mutational analysis to guide safe therapeutic switching. Discussion: Temporal association across cases and the differential kinase profiles of implicated drugs suggest PDGFR (and to a lesser extent, c-KIT) inhibition as a plausible mechanistic driver of TKI-associated BME. PDGFR-β blockade may impair pericyte-mediated microvascular integrity, increase interstitial fluid extravasation, and alter osteoblast/osteoclast coupling, promoting intramedullary edema. Management combining MRI confirmation, temporary TKI suspension, bone-directed therapy (bisphosphonates, vitamin D/calcium), symptomatic care, and, when required, therapeutic switching to a PDGFR-sparing agent (bosutinib) led to clinical recovery and preservation of leukemia control in our series. Conclusions: BME is an underrecognized, potentially disabling, TKI-related adverse event in CML. Prompt recognition with targeted MRI and a multidisciplinary, stepwise approach that includes temporary TKI adjustment, bone-directed therapy, and consideration of PDGFR-sparing alternatives can mitigate morbidity while maintaining disease control. Prospective studies are needed to define incidence, risk factors, optimal prevention, and management strategies.
    Keywords:  CML therapy; CML toxicities; bone marrow edema; bosutinib; chronic myeloid leukemia; magnetic resonance imaging; platelet-derived growth factor receptor α and β; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3390/diagnostics15243112
  6. Blood. 2026 Jan 01. 147(1): 4-5
    How blasts get into the skin-and how to get rid of them.
    Christoph Schmid.
      
    DOI:  https://doi.org/10.1182/blood.2025031448
  7. Am J Hematol. 2025 Dec 29.
    Extramedullary Disease-Achilles Heel in Myeloma?
    Shaji Kumar, Joshua Richter, Saad Z Usmani, Yael C Cohen, Jing Christine Ye, María-Victoria Mateos, Vania Hungria, Elena Zamagni.
      Despite advances in therapy, extramedullary disease (EMD) remains an aggressive form of multiple myeloma associated with poor outcomes. Patients with true EMD, in which plasmacytomas have become completely independent of bone, have a particularly poor prognosis. The pathogenesis of EMD is driven by complex mechanisms involving loss of adhesion molecules, heterogeneous genetic and epigenetic changes, and a solid tumor-like architecture within the microenvironment. Although the introduction of advanced imaging techniques and immunotherapy has led to improved detection and more promising outcomes and regimens, respectively, more prospective studies dedicated to true EMD are needed.
    Keywords:  bispecific antibodies; immunotherapy; paramedullary; relapsed myeloma
    DOI:  https://doi.org/10.1002/ajh.70138
  8. Front Pediatr. 2025 ;13 1715087
    Mixed phenotype acute leukemia, the dissection of an enigmatic disease in the era of novel therapies.
    Magdalena Karasek, Izabela Kubiszewska, Marta Sobas.
       Background: Mixed-phenotype acute leukemia (MPAL) is a rare and heterogeneous subtype of acute leukemia, associated with unfavorable outcomes. MPAL is defined by the presence of more than 20% blasts and bi- or trilineage assignment based on strong immunophenotypic markers, with specific subcategories characterized by BCR::ABL1, KMT2A, ZNF384, or BCL11B rearrangements. This review aims to summarize current knowledge and challenges in the diagnosis and management of MPAL.
    Methods: Data were synthesized primarily from meta-analyses and original studies, with a particular emphasis on the roles of immunophenotyping, cytogenetics, and novel targeted therapies from 1985 to the present.
    Results: MPAL accounts for 1%-5% of acute leukemias, with B/myeloid (59%) and T/myeloid (35%) subtypes being the most prevalent. Cytogenetic abnormalities are identified in up to 90% of cases, predominantly complex karyotypes. Molecular investigations have identified frequent mutations in genes such as RUNX1, DNMT3A, IDH1/2, NOTCH1, and FLT3, particularly enriched in T/myeloid MPAL. Adverse prognostic factors include KMT2Ar, elevated leukocyte counts, extramedullary disease, and bilineage disease biology. Generally, the prognosis for adults is poorer than for the pediatric population. No standardized treatment strategy has been established. Retrospective analyses indicate superior complete remission rates and overall survival with ALL-based regimens, and allogeneic hematopoietic stem cell transplantation remains crucial for improving survival. Recently, hybrid regimens such as FLAG-IDA and CLAG-M have demonstrated promising efficacy with acceptable toxicity. Targeted therapies are emerging options, although lineage switch under selective therapeutic pressure remains a concern.
    Conclusions: MPAL remains a significant challenge in diagnosis and treatment. Advances in molecular characterization have enhanced classification techniques and have the potential to inform personalized treatment strategies. Considering the rarity and heterogeneity of MPAL, extensive prospective multicenter trials are imperative to develop evidence-based therapeutic protocols.
    Keywords:  acute leukemia of ambiguous lineage; genetic variability; mixed-phenotype acute leukemia; outcome; targeted therapy
    DOI:  https://doi.org/10.3389/fped.2025.1715087
  9. Cancers (Basel). 2025 Dec 09. pii: 3940. [Epub ahead of print]17(24):
    Rapid Hematological and Molecular Response to Pegylated Interferon in WHO-Defined Pre-Fibrotic Myelofibrosis.
    Sigrid Machherndl-Spandl, Marcel Kiehberger, Veronika Sygulla, Emine Kaynak, Otto Zach, Gerald Webersinke, Christine Gruber-Rossipal, Christine Beham-Schmid, Eva Maier, Irene Strassl, Johannes Clausen, Alexander Nikoloudis, Wolfgang Schimetta, Holger Rumpold, Veronika Buxhofer-Ausch.
      Background: Pre-fibrotic myelofibrosis (pre-PMF) is a rare subentity of myeloproliferative neoplasm (MPN) with limited overall survival and the potential for progression toward overt, symptomatic myelofibrosis or blastic transformation. To date, a consensus on the treatment of pre-PMF, especially in asymptomatic cases, has yet to be reached. Interferon therapy has been employed as an effective treatment for MPN for many decades, due to its immunomodulatory properties and disease-modifying effects. Methods: The objective of this monocentric study was to evaluate hematological, molecular, and clinical responses, as well as the overall outcome, to pegylated interferon (peginterferon) in pre-PMF cases harboring a JAK2 or CALR mutation. Results: In a cohort of 55 consecutive patients with a median follow-up period of 3.89 (1.63; 6.10) years, a high rate of complete hematological response (81%) was documented after 24 months. Deep molecular responses with a >50% reduction in allele burden were documented in 54.6% of the JAK2-mutated and 7.7% of CALR-mutated patients, respectively (p = 0.023). Concerning fibrosis, at least the stabilization of disease was achieved in 73% of evaluable patients. Furthermore, only one case of blastic transformation was observed, along with three cases of thromboembolic events in the JAK2-mutated cohort. Conclusions: The study confirms the substantial efficacy of interferon in pre-PMF patients with rapid hematological normalization in most patients. Molecular responses were striking, but largely confined to JAK2-mutated patients. To our knowledge, this is the largest retrospective cohort of strictly WHO-defined pre-PMF patients treated with interferon and observed for a reasonable duration of time.
    Keywords:  molecular response; peginterferon; pre-PMF
    DOI:  https://doi.org/10.3390/cancers17243940
  10. Acta Pharm Sin B. 2025 Dec;15(12): 6739-6740
    CELMoD-antibody conjugates unlock a CD38 feedback loop in multiple myeloma.
    Jian Jin.
      
    Keywords:  Cereblon E3 ligase modulators; Degrader–antibody conjugate; Molecular glue; Multiple myeloma; Positive feedback; Targeted protein degradation
    DOI:  https://doi.org/10.1016/j.apsb.2025.11.017
  11. Anticancer Res. 2026 Jan;46(1): 135-141
    Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability.
    Yuta Miyashi, Kohei Mizuta, Yohei Asano, Byung Mo Kang, Jin Soo Kim, Qinghong Han, Shukuan Li, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.
       BACKGROUND/AIM: Recently, there have been numerous publications on the induction of ferroptosis by cysteine restriction in cancer cells. The present report aimed to determine whether cysteine restriction (CR) is a cancer-specific vulnerability in comparison with methionine restriction (MR), which is a known cancer-specific vulnerability.
    MATERIALS AND METHODS: Human cancer cell lines (HCT116 colon cancer, 143B osteosarcoma or HT1080 fibrosarcoma) and normal human fibroblasts (Hs27) were cultured in Dulbecco's modified Eagle's medium (DMEM) with dialyzed fetal bovine serum from which methionine or cysteine or both or neither had been depleted. Cancer and normal cells were co-cultured in 12-well plates under the above conditions. HCT116 cells expressing green fluorescent protein, and 143B and HT1080 cells expressing red fluorescent protein, were visualized by fluorescence microscopy. Normal fibroblasts and cancer cells were visualized by phase-contrast microscopy as well.
    RESULTS: In co-culture, of either 143B, HCT116 or HT1080 with Hs27 human fibrosarcoma, CR was toxic to Hs27 normal fibroblasts as well as to all three cancer cell lines. In contrast, MR was toxic only to the cancer cells but not normal fibroblasts. Dual CR and MR was toxic to normal and cancer cells.
    CONCLUSION: For all three cancer cell lines, HCT116 colon cancer, HT1080 fibrosarcoma and 143B osteosarcoma, both MR and CR were highly inhibitory in the co-cultures with Hs27 normal fibroblasts. In all cases MR had only a slight effect on normal fibroblasts, but CR was highly toxic to normal fibroblasts. Thus, MR is a cancer-specific vulnerability in contrast to CR which is toxic to both normal and cancer cells and is not a cancer-specificity vulnerability. Therefore, attempting to induce ferroptosis of cancer cells by CR does not appear to have potential as an effective cancer therapy.
    Keywords:  143B osteosarcoma cells; Cysteine; HCT116 colon cancer cells; HT1080 fibrosarcoma cells; Hs27 human normal fibroblasts; cancer-specific vulnerability; co-culture; dependence; methionine
    DOI:  https://doi.org/10.21873/anticanres.17929
  12. Int J Clin Pharmacol Ther. 2025 Dec 30.
    Parenteral replacement therapy with iron dextran or ferumoxytol in patients with iron deficiency.
    Giampaolo Talamo, Rintaro Onishi, Rahul Anand, Sundeep Bekal, Joseph Kuruvilla, Muneer Khan, Marcelle G Meseeha, Kelly L Wurzler.
       OBJECTIVE: To evaluate the changes in hematological parameters after replacement therapy with either iron dextran or ferumoxytol in patients with iron deficiency.
    MATERIALS AND METHODS: We conducted a retrospective review of 246 consecutive patients with iron deficiency treated with a single intravenous (IV) infusion of a fixed dose of 1,025 mg of iron dextran (145 patients) or 1,020 mg of ferumoxytol (101 patients). Laboratory data were collected at baseline and at 2 - 3 months after replacement therapy.
    RESULTS: The median hemoglobin (Hb) and ferritin levels pre- and post-iron dextran were 9.5 (95% CI, 9.2 - 10.0) g/dL and 17 (95% CI, 14 - 20) ng/mL, and 12.0 (95% CI, 11.7 - 12.2) g/dL (p < 0.0001) and 123 (95% CI, 98 - 162) ng/mL (p < 0.0001), respectively. The median Hb and ferritin levels pre and post ferumoxytol were 10.4 (95% CI, 9.8 - 10.9) g/dL and 22 (95% CI, 18 - 28) ng/mL, and 12.5 (95% CI, 12.1 - 12.9) g/dL (p < 0.0001) and 129 (95% CI, 90 - 174) ng/mL (p < 0.0001), respectively. No statistically significant difference was observed between iron dextran and ferumoxytol in change of Hb levels, ferritin, transferrin saturation, mean corpuscular volume (MCV), and red cell distribution width (RDW). Transfusion reactions with iron dextran and ferumoxytol were observed in 2 (1.4%) and 3 (3%) patients, respectively (p = 0.65).
    CONCLUSION: In patients with iron deficiency, the change of the hematological parameters after replacement therapy was not statistically different between iron dextran and ferumoxytol. Our data suggests that these two formulations have similar efficacy and safety after the IV administration of equivalent doses.
    DOI:  https://doi.org/10.5414/CP204904
  13. J Biol Chem. 2025 Dec 30. pii: S0021-9258(25)02979-5. [Epub ahead of print] 111127
    Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity.
    Yuou Wang, Anish Sen-Majumdar, Jian-Ming Li, Srijon Sarkar, Tenzin Passang, Sonia Mecorapaj, Swapnaa Balaji, Tenzin Kalsang, Antonio B Ward, Yiwen Li, Jamie Cohen, Zihan Chen, Kiranj Chaudagar, Pankoj Kumar Das, Shuhua Wang, Nabute Bruk, Nikolaos Papadantonakis, Cynthia R Giver, Edmund K Waller.
      Vasoactive intestinal peptide (VIP) is a neuropeptide involved in cancer proliferation and immune suppression. The limited potency of the VIP antagonist peptide VIPhyb in T-cell activation and murine anti-leukemia models prompted the development of a more potent antagonist. We screened a combinatorial library of VIPhyb C-terminal peptide sequence variants to identify a higher-affinity VIP-receptor (VIP-R) antagonist, hypothesizing that specific amino acid substitutions could improve receptor binding and/or plasma stability. In silico screening analyses identified sequences with docking scores predicting increased binding affinity to human VIP receptors VPAC1 and VPAC2. Fifteen peptides were synthesized and tested for their ability to potentiate activation of purified mouse and human T cells and enhance T cell-dependent anti-leukemia responses in murine acute myeloid leukemia models. Treating C57Bl/6 mice engrafted with a C1498 leukemia cell line with daily subcutaneous injections of VIP-R antagonist peptides induced anti-leukemia responses. Strikingly, the predicted binding s of the VIP-R antagonists to VIP receptors correlated positively with their ability to augment mouse T-cell proliferation and anti-leukemia activity. ANT308 and ANT195 emerged as top candidates due to high predicted VIP-R binding, low EC50 for in vitro T cell activation, and potent anti-leukemia activities. ANT308 decreased CREB phosphorylation, a downstream signaling pathway of the VIP receptor, and stimulated granzyme B and perforin expression in CD8+ T cells from AML patients. Combining in silico modeling, in vitro T cell activation properties, and in vivo anti-leukemia activity has identified promising VIP-R antagonist candidates for further development as novel immunotherapies for AML patients with relapsed disease.
    DOI:  https://doi.org/10.1016/j.jbc.2025.111127
  14. J Am Chem Soc. 2026 Jan 02.
    Polymeric Lysosome-Targeting Chimeras (PolyTACs): Extracellular Targeted Protein Degradation without Co-Opting Lysosome-Targeting Receptors.
    Ryan Hung-Hsun Lu, Jithu Krishna, Yasin Alp, S Thayumanavan.
      Extracellular targeted protein degradation (eTPD) is an emerging modality to regulate protein levels without genomic interruption. Current strategies co-opt lysosome-targeting receptors (LTRs) that are ubiquitously present in most cells, offering a high success rate of eTPD across cell types and tissues. To circumvent on-target, off-site protein degradation, exploring alternative strategies is becoming a main focus to advance conventional platforms. Until now, many efforts have been focused on developing degraders by repurposing the surface receptors with intrinsically internalizing function. Yet, exploring novel access to eTPD would introduce an arguably nimble molecular design paradigm that opens up new opportunities in many diseases without such receptor availability. Opening up the binding complementarity requirement from LTRs to any overexpressed cell surface receptor offers to endow eTPD platforms with new cellular targeting capabilities. Here, we report polymeric lysosome-targeting chimeras (PolyTACs), a polymer-antibody conjugate based platform for the targeted degradation of membrane-bound and soluble proteins without the need for involving LTRs. Mechanistic investigations suggest a nonclassical uptake pathway caused by the multivalent interactions between the PolyTACs and the overexpressed functionalities on the cell surface. The utility of PolyTACs in eTPD has been demonstrated with four disease-relevant membrane proteins. Additionally, the same design principle has also been leveraged to bind and drag soluble extracellular proteins into the lysosome. The design and fabrication simplicity, nonreliance on LTRs, and tissue-targeting capabilities open up new avenues for eTPD in many disease-specific applications.
    DOI:  https://doi.org/10.1021/jacs.5c17519
  15. J Med Chem. 2026 Jan 03.
    Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies.
    John M Hatcher, Shirong Liu, Amanda Kofides, Alexa Canning, Dominic Pizzarella, Xia Liu, Nickolas Tsakmaklis, Maria Guerrera, Christopher Patterson, Alberto Guijosa, Prafulla Gokhale, Zachary Hunter, Shayna Sarosiek, Jorge Castillo, Jinhua Wang, Sara J Buhrlage, Steven P Treon.
      Hematopoietic cell kinase (HCK) and Bruton tyrosine kinase (BTK) are critical drivers of survival signaling in MYD88-mutated (MYD88Mut) lymphomas. Building on our previously developed dual HCK/BTK inhibitor KIN-8194, we designed DFCI-002-06, a first-in-class proteolysis-targeting chimera (PROTAC) that potently and selectively degrades both kinases while retaining kinase inhibitory activity with improved selectivity versus KIN-8194. DFCI-002-06 induced enhanced apoptosis in MYD88Mut lymphoma cells and remained active against ibrutinib-resistant BTKCys481 variants. The compound demonstrated high oral bioavailability in mice (F = 39%), favorable pharmacokinetics, and dose-dependent degradation of HCK and BTK in tumors. In TMD8 xenograft models, orally dosed DFCI-002-06 produced superior tumor suppression and prolonged survival compared to KIN-8194. Preclinical safety studies showed a favorable profile, including a negative Ames test, no hERG inhibition at relevant concentrations, and excellent tolerability in a 21 day rat toxicity study. DFCI-002-06 represents a rational dual-target degradation strategy for MYD88Mut lymphomas.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c02444
  16. J Clin Med. 2025 Dec 08. pii: 8681. [Epub ahead of print]14(24):
    How to Read a Next-Generation Sequencing Report for AML and MDS? What Hematologists Need to Know.
    Salvatore Perrone, Cristina Tresoldi, Silvia Rigamonti, Matteo Molica, Nadezda Zhdanovskaya, Laura Cicconi.
      Acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are clonal hematopoietic malignancies in which next-generation sequencing (NGS) has become integral for diagnosis, classification, risk stratification, and measurable residual disease (MRD) monitoring. Traditional cytogenetic and PCR-based assays remain useful, but targeted NGS panels now represent the standard of care, providing rapid and sensitive detection of recurrent gene mutations, structural variants, and gene fusions. Whole-genome, whole-exome, and RNA sequencing and long-read platforms expand the spectrum of detectable alterations, though targeted panels remain most practical for routine diagnostics. Bioinformatic pipelines and quality metrics-including read length, sequencing depth, and coverage-are critical for accurate variant calling, with validation often required for variants of uncertain significance or those near detection thresholds. NGS is now embedded in diagnostic frameworks, including the WHO 2022 and ICC classifications, which incorporate recurrently mutated genes such as TP53, ASXL1, RUNX1, and FLT3. These data inform prognostic models, with ELN-2022 defining adverse-risk AML subgroups for patients treated with intensive chemotherapy, ELN-2024 AML for patients treated with less-intensive therapies, and the IPSS-M refining MDS risk categories by integrating mutational data. NGS also enables MRD monitoring, with gene panels and PCR-NGS hybrid approaches (e.g., for FLT3-ITD) showing increasing clinical utility, though standardization is still lacking. Furthermore, diagnostic NGS frequently uncovers germline predisposition syndromes (e.g., DDX41, GATA2), with significant implications for treatment decisions and donor selection in transplantation. In this manuscript, we review the advantages, limitations, and future perspectives of NGS in the clinical management of AML and MDS with a particular emphasis on the biological and technical principles underlying its use in these diseases. Furthermore, we discuss how NGS findings may influence diagnosis, prognostic classification, and therapeutic decision-making within current clinical frameworks. Our aim is to provide a comprehensive overview of NGS fundamentals to support clinicians in navigating the increasing complexity of molecular data in daily practice.
    Keywords:  NGS-report; acute myeloid leukemia (AML); germline predisposition to myeloid neoplasms; measurable residual disease (MRD); myelodysplastic neoplasms (MDS); next-generation sequencing (NGS)
    DOI:  https://doi.org/10.3390/jcm14248681
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