Blood最新文献

Pediatric hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, characterized by heightened T-cell activation and overwhelming IFN-g production. Rather than a binary "primary" versus "secondary" framework, it is best conceptualized as a threshold phenomenon that occurs when combined genetic and environmental factors exceed a critical tipping point, leading to a recognizable clinical pattern of abnormal immunopathology. In addition to classic genetic cytotoxic defects, an increasing number of genetic lesions continue to be recognized related to HLH. Environmental triggers frequently include malignancy, infection, and rheumatologic disorders and identifying underlying factors driving HLH is a crucial component of evaluation. The revised HLH-2004 criteria are an important tool in promptly recognizing HLH, but clinical criteria may be fulfilled by other inflammatory disorders. Genetic and functional immune testing are complementary tools for diagnosis and establishing recurrence risk. Dexamethasone and etoposide remain cornerstones of initial therapy but are best utilized in an individualized, response-based manner with close monitoring of inflammatory markers. Newer, more targeted agents continue to emerge and are often critical additions for achieving disease control. Most patients with inherited cytotoxic defects and other select causes require hematopoietic cell transplant (HCT) for cure which should occur as soon as feasible once adequate, not perfect, HLH control aims to minimize risk of reactivation, infection, and toxicity. This review aims to highlight key advancements in defining, diagnosing, and treating HLH based on a growing understanding of HLH pathophysiology. We also provide perspectives on practical clinical approaches that may be useful for diagnosing and treating pediatric HLH.

Sickle cell nephropathy (SCN) is a major clinical complication in sickle cell disease (SCD), yet its underlying mechanisms remain incompletely defined. Hemolysis, a hallmark of SCD, has been implicated in SCN pathogenesis, but the downstream inflammatory pathways are not fully understood. We previously demonstrated that hemolysis triggers type I interferon (IFN-I) responses, leading to upregulation of the chemokine CCL2 and recruitment of classical monocytes that differentiate into monocyte-derived macrophages (MoMϕ) within livers in SCD. In this study, we show that IFN-I and CCL2 levels are elevated in the plasma of SCD patients with abnormal urine albumin-creatinine ratio (uACR) and in the kidneys of Townes SCD mouse model. Using IFN-I receptor (Ifnar1)-/- and CCL2 receptor (Ccr2)-/- mouse models of SCD, we demonstrate that loss of IFN-I or CCL2 signaling reduces MoMϕ accumulation, renal inflammation, and renal injury. Mechanistically, we identify that hemin-induced IFN-I production occurs via the TLR3/TRIF signaling axis, independent of MyD88, MAVS, or STING. These findings uncover a previously unrecognized heme-TLR3/TRIF-IFN-I-CCL2 pathway that contributes to renal pathology in SCD and suggest that targeting this axis may offer therapeutic benefit.

Somatic frameshift mutations in the gene encoding calreticulin (CALR) give rise to myelofibrosis and are classified as Type 1 (del52) or Type 2 (ins5) according to the degree of wildtype sequence retained adjacent to the neopeptide, with each type conferring different clinical outcomes. Targeting strategies specific for Type 1 vs Type 2 mutations would have enormous clinical utility in the treatment and prevention of myelofibrosis as responses to tyrosine kinase inhibitors are not durable nor mutation-specific. Here we show that dual targeting of Type 1 (del52) mutant CALR with two monoclonal antibodies directed against distinct epitopes in CALR have significant advantages compared to single agent treatment in the eradication of primary megakaryocyte progenitors in vitro and in a humanized ossicle microenvironment leading to improved survival in xenograft models. Dual targeting was superior in blocking constitutive STAT5 and ERK phosphorylation induced by del52 and prevented accumulation of JAK2 phosphorylation, overcoming ruxolitinib resistance. In contrast, Type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting but could be impacted by ruxolitinib triple combination. Together, our data demonstrate an ultra-precision medicine approach tailored to either Type 1 OR Type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signalling, with far-reaching implications for patient management.

Heatstroke, a severe hyperthermic condition, is characterized by a core body temperature exceeding 40℃ and multiple organ dysfunction syndrome (MODS) with an extremely high mortality rate. Despite advances in identifying heatstroke-induced cell death pathways, the molecular cascades that bridge heat-induced cell death to MODS and mortality are not yet fully characterized. Our findings demonstrate that Z-DNA binding protein 1 (ZBP1)-triggered disseminated intravascular coagulation critically drives MODS and fatal outcomes in heatstroke. Heat stress activates ZBP1-dependent necroptosis, promoting tissue factor (TF) release and phosphatidylserine (PS) externalization. Genetic knockout of ZBP1 or its downstream necroptotic effectors, reduction of global TF expression, suppression of PS exposure, or pharmacological inhibition of the coagulation cascade attenuates heat stress-induced coagulation activation, organ injury, and death. Comparable results are obtained in heat-stressed mice with conditional knockout of ZBP1 in hematopoietic or myeloid lineages. Overall, our study reveals the critical role of ZBP1-mediated necroptosis in bridging heat stress and coagulation dysfunction.

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.