Resistance to regulated cell death is one of the hallmarks of human cancers; it maintains cell survival and significantly limits the effectiveness of conventional drug therapy. Leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance. As the majority of chemotherapeutic and targeted drugs kill leukemia cells by triggering apoptosis, the observed resistance indicates the need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia. Necroptosis is a regulated form of necrosis that is precisely modulated by intracellular signaling pathways and thus provides potential molecular targets for rational therapeutic intervention. Indeed, accumulating evidence indicates that many current antitumor agents can activate necroptotic pathways and thereby induce leukemia cell death. Elucidation of the complete regulatory mechanism of necroptosis is expected to accelerate the development of novel therapeutic strategies for overcoming apoptosis resistance in leukemia. Here, we review the latest research advances in the regulatory mechanisms of necroptosis and summarize the progression of necroptosis-based therapeutic strategies in leukemia.

MYD88/CD79B-mutated (MCD) genotype is a genetic subgroup of diffuse large B-cell lymphoma (DLBCL) with the co-occurrence of MYD88^L265P and CD79B mutations. MCD genotype is characterized by poor prognosis and extranodal involvement especially in immune-privileged sites. MCD model is dominated by activated B-cell (ABC)-like subtype of DLBCLs. It is generally accepted that the pathogenesis of MCD DLBCL mainly includes chronic active B-cell receptor (BCR) signaling and oncogenic MYD88 mutations, which drives pathological nuclear factor kappa B (NF-κB) activation in MCD lymphoid malignancies. CD79B and MYD88^L265P mutations are frequently and contemporaneously founded in B-cell malignancies. The collaboration of the two mutations may explain the unique biology of MCD. Meanwhile, standard immunochemotherapy combine with different targeted therapies worth further study to improve the prognosis of MCD, according to genetic, phenotypic, and clinical features of MCD type. In this review, we systematically described mechanism, clinical characteristics, and targeted therapy of MCD DLBCL.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome, and the overall survival (OS) of adult patients is poor. Ruxolitinib, a Janus kinase 1/2 (JAK1/2) inhibitor, has shown promise in treating HLH and exerts synergistic effects when combined with dexamethasone. Our pilot study preliminarily demonstrated that the combination of ruxolitinib and dexamethasone (Ru-D regimen) had a high response rate and led to favorable short-term survival outcomes in adult patients with HLH. In this prospective phase 2 clinical trial, we propose the Ru-D regimen as a first-line treatment for adults newly diagnosed as having HLH with unknown triggers. A total of 28 Chinese patients were enrolled, and the median follow-up time was 25.1 months (range, 0.87-34.0). The 2-month OS rate (the primary end point) was 85.7%, which exceeded our expected 2-month OS rate of 75%. The 6-month and 2-year OS rates were 67.9% (19/28) and 53.6% (15/28), respectively. The median OS of patients with lymphoma-associated HLH (LAHS) was 5.8 months, and most of these patients had natural killer/T-cell lymphoma. In contrast, the 2-year OS rate of patients without LAHS was 75%. The overall response rate was 85.7% (24/28); of 28 patients, 5 (17.9%) achieved a complete response during the Ru-D regimen. Overall, the Ru-D regimen was well tolerated in patients with HLH. This study demonstrates the efficacy and safety of the Ru-D regimen in adults newly diagnosed as having HLH with unknown triggers and warrants a phase 3 randomized controlled study. This trial was registered at www.chictr.org.cn as #ChiCTR2100049996).

Background: The differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL). Methods: We analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph⁺ ALL treated with chemotherapy plus tyrosine kinase inhibitors. We also studied transcriptome features in two newly diagnosed patients with p190 and p210 using single-cell RNA sequencing (scRNA-seq). Results: P190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p = 0.05), platelet count (p = 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p = 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225K/V mutations (91.3% vs. 68.6%; p = 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1%; p = 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0%; p = 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS: 10.4% vs. 9.2%, p = 0.069, 3-year OS: 44.3% vs. 38.2%, p = 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS [HR 1.692 (95% CI 1.009–2.838), p = 0.046]. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts. Conclusions: Ph⁺ ALL patients with p190 and p210 had different clinical characteristics, outcomes, ABL1 mutation profiles, and transcriptome features. Allo-HSCT could improve the outcomes of patients with p210.

Development of resistance to tyrosine kinase inhibitors (TKIs) targeting the BCR/ABL fusion protein represents a major challenge in the treatment of chronic myeloid leukemia (CML). Since apoptosis resistance is the fundamental mechanism impeding TKIs’ therapeutic effects, alternative approaches that induce nonapoptotic cell death are being pursued to treat TKI-resistant CML. Induction of necroptosis, a distinct, caspase-independent form of programmed cell death, may be a valuable strategy in this respect. The present study shows that shikonin, an herbal compound used in traditional Chinese medicine, overcomes TKI resistance in BCR/ABL-positive CML cells by inducing necroptosis via activation of RIPK1/RIPK3/MLKL signaling. This effect occurs both in vitro and in vivo and involves downregulation of miR-92a-1-5p, a poor-prognosis marker frequently overexpressed in leukemia patients. Based on gene expression experiments, we conclude that miR-92a-1-5p promotes CML progression by inhibiting MLKL expression. Accordingly, we show that antagomiR-mediated in vivo inhibition of miR-92a-1-5p reduces the growth of CML tumors in mice through necroptosis induction. Our research suggests that therapies that relieve MLKL suppression by targeting miR-92a-1-5p may represent a useful strategy to treat TKI-refractory CML.