Leukemia最新文献

Clonal hematopoiesis (CH) is a non-malignant clonal expansion of a hematopoietic stem cell population due to the acquisition of somatic mutation(s) that confer advantages in self-renewal and proliferation. These mutations have been detected in healthy individuals and rise in frequency with normal aging [1]. The increase in prevalence of CH with age may reflect the cumulative effect of exposures to environmental stressors, such as radiation, tobacco, and mutagenic drugs, that provide selective pressure for particular hematopoietic stem cells and consequent clonal expansion [2]. Although its presence does not directly lead to oncologic disease, CH has been associated with an increased risk of hematologic malignancies and myeloid neoplasms (MNs), chronic inflammation, and cardiovascular complications [3].

The Clonal Hematopoiesis Risk Score (CHRS) is a personalized prediction tool incorporating age, peripheral blood laboratory values, specific mutations, and variant allele frequency (VAF) to assess the risk of progression to MNs in healthy adults with CH [4]. The impact of medical histories, especially prior cancer diagnosis and exposure to antineoplastic therapy, is not included. Additionally, although it is well established that CH increases risk of MN transformation, the dynamics of disease evolution in patients with CH who progress to MNs remain unknown. Thus, we aimed to evaluate the clinicopathologic characteristics and survival outcomes of patients with MN with known antecedent CH, with a particular focus on patients with prior non-myeloid malignancies.

Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.

Internal tandem duplication mutations in the FMS-like tyrosine kinase 3 (FLT3-ITDs) occur in 25%–30% of acute myeloid leukemia (AML) cases and are associated with adverse prognosis. RNA-based therapeutics exhibit significant potential for treating diseases, prompting us to develop a novel circular RNA (circRNA)-based therapeutic strategy for FLT3-ITD AML. Here, we find circTADA2A is downregulated in FLT3-ITD AML patients. We further demonstrate that the downregulation of circTADA2A is critical for the proliferation of human FLT3-ITD AML cells, the sustenance of AML, and the self-renewal of leukemia stem/initiating cells (LSCs/LICs). Mechanistically, circTADA2A inhibits the TRIM28/MDM2 complexes formation by competitively binding to TRIM28, resulting in decreased levels of p53 ubiquitination and activating the p53 pathway. Importantly, in vitro transcription of circTADA2A and in vivo delivery via lipid nanoparticles (LNPs) significantly enhance the elimination of FLT3-ITD leukemia cells in combination with quizartinib treatment. In conclusion, our work uncovers the crucial functions of circTADA2A in the maintenance of FLT3-ITD AML and highlights a translationally important circTADA2A-based therapeutic approach for FLT3-ITD AML treatment.

Acute myeloid leukemia stem cells (LSCs) express major histocompatibility complex (MHC) class I and II and many different immune checkpoint ligands and receptors, in which respect they resemble professional antigen-presenting cells. In addition, LSCs reside in the bone marrow (BM), a primary and secondary lymphoid organ, surrounded by immune cells. The function of these immune checkpoints (ICs) in the regulation of an anti-tumor immune response is well studied and IC inhibitors (ICIs) became a standard of care in many solid tumors. However, ICIs have very limited efficacy in AML. Nevertheless, the expression especially of immune activating ligands and receptors on LSCs is somewhat unexpected, since these cells have to evade protective immunity. Many ICs have been shown to mediate direct signaling in AML blasts and LSCs and thereby regulate self-renewal, differentiation and expansion of leukemic cells. Thus, the expression of ICs on the cell surface or their soluble forms often correlate with worse survival. In this review we summarize recent data on selected ICs of the immunoglobulin superfamily (IgSF) and the tumor necrosis factor receptor superfamily (TNFRSF) that have a documented role in the regulation of LSCs, independent of their immune regulatory role, and might become novel therapeutic targets.

Over 60% of relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with chimeric antigen receptor (CAR) T-cells experience progressive disease. The impact of site-specific extranodal involvement on CAR-T outcomes has not been fully elucidated. This multicenter study included 516 R/R LBCL patients infused with CD19-targeted CAR T-cells; 177 (34%) had only-nodal (N), 66 (13%) only-extranodal (E) and 273 (53%) nodal and extranodal (NE) disease at time of CAR T-cells. The NE cohort included more patients with a poor performance status and high tumor burden. In the multivariable analysis, the NE group had a shorter progression-free survival (PFS) (HR 1.27 [95%CI 0.98–1.64], p = 0.07) and overall survival (HR 1.41 [95%CI 1.05–1.88], p = 0.02) compared to N. Conversely, we did not identify efficacy differences between N and E patients. A higher number of extranodal sites and specific organ involvement (liver, adrenal glands, pancreas), were associated with shorter PFS. Finally, extranodal involvement increased at time of relapse, displaying heterogeneous individual site clearance rates. In conclusion, patients with concomitant nodal and extranodal involvement at time of CAR-T had worse outcomes, but this cohort harbored high-risk baseline characteristics. An increasing number of extranodal sites and certain disease locations were associated with lower CAR-T efficacy.

Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.

Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of hematopoietic stem cells, which can lead to secondary myelofibrosis or acute myeloid leukemia. We explored the changes in genomic alterations during MPN transformation using whole-genome sequencing of samples from both the chronic and fibrotic or leukemic phases of 20 patients. We identified FOXP1 mutations in 3 of 14 (21.4%) patients with secondary myelofibrosis. This novel mutation was identified in another 5 of the 35 patients (14.3%) in an independent cohort. All these 8 patients with FOXP1 mutations did not experience leukemic transformation after a median follow-up of 5.1 years. The acquisition of non-canonical MPL^Y591 mutations was detected in the fibrotic or leukemic phase. Clonal expansion, involving both known and unknown driver genes (in 18 and 2 patients, respectively), was observed in all patients. We determined the patterns of clonal evolution based on myeloid driver mutations in 18 patients: linear clonal evolution in 11 patients and branched clonal evolution in 7 patients. Our results suggested that MPN patients carrying FOXP1 mutations are unlikely to have leukemia transformation and emphasized that the acquisition of specific genetic mutations and dynamic changes in clonal architecture underlie the pathogenesis in patients undergoing MPN transformation.