Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1–C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1–C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

Raman spectroscopy (RS) can provide fingerprint-type information on biochemical molecules. RS-based blood plasma analysis of solid tumors has been reported in recent years; however, there are no studies on the use of this analysis for detecting blood diseases. We studied the features of blood plasma in patients with diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) by RS with the aim of developing a simple blood test for noninvasive DLBCL and CLL detection. We analyzed blood plasma from 33 DLBCL patients, 39 CLL patients and 30 healthy volunteers. Orthogonal partial least squares discriminant analysis (OPLS-DA) could build two clusters with almost no overlap between DLBCL/CLL and the controls. We used the prediction set to test the model built by OPLS-DA. For the CLL model, the sensitivity was 92.86%, and the specificity was 100%, whereas for the DLBCL model, the sensitivity was 80% and the specificity was 92.31%. We found Raman bands specific to both DLBCL and CLL patients in comparison with the healthy volunteers. Most importantly, we found that the combination of the 1445 cm^-1 and 1655 cm^-1 Raman shifts could discriminate DLBCL from CLL and even the other solid tumors reported to date. Further analysis of the assignments of 1655 cm^-1 also gave us a clue to find potential important variables hemoglobin and serum albumin related with the CLL prognosis. Our exploratory study primarily demonstrated the great potential of developing RS blood plasma analysis as a novel clinical tool for the noninvasive detection of DLBCL and CLL.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job’s syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α–stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.