MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15–20%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53...
Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous B-cell malignancy with a historically poor prognosis. Recent advances have substantially expanded treatment options, particularly through the integration of targeted therapies, chemotherapy-free regimens, and cellular approaches. Frontline treatment now incorporates Bruton’s tyrosine kinase inhibitors (BTKi...
In allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy), clinicians frequently face a critical choice between a readily available, often younger, haploidentical and a fully matched unrelated donor (MUD). The platform-specific influence of donor age on survival is a critical, unquantified factor that complicates clinical decision-making. We...
During the past 35 years, single-arm studies documented the efficacy and safety of recombinant interferon alpha (rIFNα) for treating polycythemia vera (PV). In some patients, 2-5 years of disease-modifying treatment resulted in symptom relief, regression of splenomegaly, normalization of abnormal blood counts and marrow morphology, and sustained JAK2V617F molecular remission. The...
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell lymphoma. Although many patients respond well to R-CHOP immunochemotherapy, those with the activated B-cell (ABC) subtype are often refractory or relapse. Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have improved outcomes, but acquired resistance limits their long-term efficacy. Here, we...
Ribosome collisions act as molecular sensors of cellular stress, yet their role in disease physiology remains unclear. Here, we demonstrate that inhibition of the oncogenic kinase BCR::ABL1 in chronic myeloid leukemia (CML) cells induces ribosome collisions and activates the ribotoxic stress response (RSR). Clinical analyses revealed that CML progression from the chronic phase to...
Chronic myeloid leukemia (CML) and Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are generally distinct clonal disorders, with the co-occurrence of BCR::ABL1 rearrangement with concomitant Ph-negative MPN rarely reported. Here we describe the largest known international cohort of Ph-negative MPN and coexisting CML providing important insights into this rare...
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled expansion of undifferentiated myeloid precursors in the bone marrow. Hypomethylating agents (HMAs) such as azacitidine and decitabine can reverse abnormal DNA methylation, promote leukemic cell differentiation, and enhance immune recognition, yet relapse and therapeutic...
KMT2A-rearranged acute myeloid leukemia is driven by epigenetic dependencies yet remains clinically resistant to therapies targeting individual regulators, indicating that resistance reflects compensatory regulation across an epigenetic network. A systematic understanding of this compensatory network has been lacking. To address this gap, we utilized Perturb-seq screening to...
Periconceptional folate intake decreases the risk of pediatric acute lymphoblastic leukemia (ALL); however, the mechanism is not fully understood. We sought to identify sites of DNA methylation measured at birth both responsive to periconceptional folate and associated with lymphoblasts at the time of ALL diagnosis in a “meet in the middle” analysis. Folate-associated...
The increasing therapeutic options for multiple myeloma (MM) have significantly improved long-term survival for many patients. However, disease progression remains inevitable due to the emergence of drug-resistant myeloma cell populations, often culminating in extramedullary disease manifestations. In this study, we identified CD70-expressing myeloma cells as critical drivers of...
Despite extensive research and intensive use of chemotherapies in clinics, the 5-year overall survival of acute myeloid leukemia (AML) patients does not exceed 20%. The clonal expansion of leukemic blasts leads to modifications of the bone marrow physical properties, including increased extracellular matrix stiffening, upregulation of intramedullary pressure and reduction of the...
Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However...