Hershkovitz-Rokah, Oshrat

Summary Amyloid light‐chain (AL) amyloidosis is a systemic clonal plasma cell disorder characterized by the production and deposition of misfolded immunoglobulin light chains (LCs), resulting in multiorgan dysfunction. Due to its intricate molecular mechanisms and diverse organ involvement, the disease poses significant diagnostic and therapeutic challenges. This review explores the molecular landscape of AL amyloidosis, emphasizing genetic, transcriptomic and proteomic alterations. Key findings include chromosomal abnormalities, somatic mutations, aberrant gene expression, disrupted protein folding pathways and the role of cytokine and chemokine secretion. These factors collectively drive the overproduction and destabilization of amyloidogenic LCs, leading to organ‐specific amyloid deposition, clinical heterogeneity and variable patient outcomes. Despite therapeutic advancements, the disease's complexity challenges the development of effective biological models. Progressing towards personalized therapies requires the development of preclinical models and the identification of biomarkers and molecular data to design targeted interventions. This review highlights the importance of integrating DNA, RNA and protein‐level analyses to deepen the understanding of AL amyloidosis pathogenesis. Such insights are pivotal for improving diagnostics, prognostics and therapeutic strategies, ultimately advancing precision medicine for this challenging disease.

Summary Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai–Dorfman–Destombes disease (RDD) and Erdheim–Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy‐proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty‐seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non‐V600‐BRAF, RAF1 and a BICD2‐BRAF fusion. A repeated‐measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19–137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03–0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Abstract Background Noncoding RNAs such as microRNAs (miRNAs) have attracted attention as biological pathway regulators, which differ from chromosomal translocations and gene point mutations. Their involvement in the molecular mechanisms underlying light chain (AL) amyloidosis pathogenesis is yet to be elucidated. Aims To decipher specific miRNA expression profile in AL‐amyloidosis and to examine how miRNAs are involved in AL pathogenesis. Methods The expression profile of miRNAs and mRNA from bone marrow (BM)‐derived CD138+ cells were determined using the NanoString nCounter assay and RNA‐Seq, respectively. The effect of aberrantly expressed miRNAs on potential molecular targets was analyzed by qRT‐PCR, Western blot, Mito‐potential assay, and Annexin‐PI staining. Results Genes which were significantly differentially expressed between AL‐amyloidosis and MM, were found to be involved in cell growth and apoptotic mechanisms. Specifically, BCL2L1, MCL1, and BCL2 were upregulated in AL‐amyloidosis compared with MM and controls. The levels of miR‐181a‐5p and miR‐9‐5p, which regulate the above‐mentioned genes, were lower in BM samples from AL‐amyloidosis compared with controls, providing a mechanism for BCL2 family gene upregulation. When miR‐9‐5p and miR‐181a‐5p were overexpressed in ALMC1 cells, BCL2L1, MCL1, and BCL2 were downregulated and induced apoptosis. Treatment of ALMC‐1 cells with venetoclax, (BCL‐2 inhibitor), resulted in the upregulation of those miRNAs, the downregulation of BCL2, MCL1, and BCL2L1 mRNA and protein levels, and subsequent apoptosis. Conclusion Our findings suggest that miR‐9‐5p and miR‐181a‐5p act as tumor‐suppressors whose downregulation induces anti‐apoptotic mechanisms underlying the pathogenesis of AL‐amyloidosis. The study highlights the post‐transcriptional regulation in AL‐amyloidosis and provides pathogenetic evidence for the potential use of BCL‐2 inhibitors in this disease.

Abstract Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.