Xuezhu Wang

Multiple myeloma (MM) remains incurable despite major therapeutic advances, underscoring the unmet need for earlier and genetically informed intervention. The rationale for such intervention lies in the stepwise evolution of MM from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), during which genetic alterations accumulate and drive the emergence, expansion, and evolution of malignant clones. In 2025, three landmark cohort studies using whole-exome or whole-genome sequencing (WES/WGS) proposed distinct but relevant genomic frameworks for reclassifying disease risk in MGUS and SMM. Despite differences in design and analyses, these frameworks converge on several principles: (i) the malignant genomic architecture of myeloma is established well before clinical progression; (ii) a substantial fraction of clinically defined precursor disease already harbors the hallmarks of overt myeloma; and (iii) WES/WGS-derived features meaningfully improve clinical risk models. In this perspective, we critically reviewed these three contemporaneous frameworks and synthesize their convergent implications, not previously consolidated for clinical use, into a practical approach toward genomics-guided management of myeloma precursor conditions.

Primary light-chain amyloidosis (pAL) is caused by plasma cell (PC) clones that secrete misfolded free light chains that deposit. Anti-CD38 antibody daratumumab is the first-line therapy, while ∼10–30% of patients exhibit suboptimal responses (PTGES2/3–PTGER2/4 axis driven by PTGS2 expressing myeloid-derived suppressor cell–like CD38⁻ CD14⁺ monocytes that expanded with treatment; and (ii) an immunosuppressive non-classical MHC I axis, in which PCs exerted inhibitory interactions ( HLA-E–KLRK1 , HLA-G–LILRB1 , HLA-F–LILRB1 ). Consistent with these cell-cell interactions, myeloid cells and NK cells showed functional impairment, while T cells were more exhausted; all three cell types exhibited increased interferon-γ responses in suboptimal versus good responders. This atlas reveals amyloidogenic PCs’ resistance to daratumumab and an inflammatory–immunosuppressive niche driven by prostaglandin and non-classical MHC I, underpinning suboptimal responses.

Yale School of Medicine (YSM) has consistently been at the forefront of promoting equity and inclusiveness within the realms of research and patient care. Using YSM’s official data on Asian female faculty members (2001–2024) and students (2014–2024) as a starting point, this review traces a historical narrative spanning over a century (1924–2024), shedding light on the remarkable achievements and enduring challenges faced by Asian females at YSM. The journey begins with trailblazers such as Dr. Chenghui Ge, the first Chinese woman to earn a DrPH at YSM in 1926, and Dr. Gueh Djen Hsiung, who became Yale’s first Asian female department director in 1960. Their pioneering contributions laid the foundation for future generations of Asian women in medicine. In more recent decades, this article highlights the enduring impact of leaders from YSM and spotlights emerging young physicians and scientists trained in Yale’s residency programs and clinical or research fellowships, who are making progress in the early stages of their careers, showcasing the ongoing evolution of Asian female representation at YSM. Beyond celebrating these milestones, this review amplifies the voices of YSM’s Asian women, addressing persistent challenges such as identity-based discrimination, cultural barriers, the "glass ceiling" in leadership roles, and the balancing act of family responsibilities. By documenting these achievements and struggles, this digital collection aims to share YSM’s progress and lessons learned while advocating for greater awareness of how cultural identity shapes academic and professional advancement.

Plasma cell disorders (PCDs) are marked by the clonal proliferation of abnormal plasma cells and bone marrow plasma cells (BMPCs), causing various clinical complications. These PCDs include subtypes with distinct clinical features. Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are more common and relatively well-studied. In contrast, primary light-chain amyloidosis (AL) and POEMS syndrome (POEMS) are rare and remain less understood. To investigate the role of clonal hematopoietic (CH) mutations and potential interconnections in these diseases, we sequenced CH mutations in lymphoid and myeloid lineages, as well as myeloma driver gene mutations, in BMPCs from affected patients. Recurrent lymphoid CH mutations (in FAT1, KMT2D, MGA, and SYNE1) and myeloma driver gene mutations (in ZFHX3 and DIS3) were found in the dominant clonal and subclonal plasma cell populations. These moderately aging-associated lymphoid CH mutations had a higher burden in MM than in AL or POEMS. Binary matrix factorization of these mutations revealed the subgroups associated with progression-free survival (PFS) (observed in MM, AL, and POEMS), age at diagnosis (in AL and POEMS), serum differential free light chain (dFLC) levels, plasma cell burden (in AL), and serum vascular endothelial growth factor (VEGF) levels (in POEMS). Moreover, the poor PFS associated with MGA or SYNE1 mutations was confirmed across MM, AL, and POEMS. CH mutations partially explained the shared pathogenesis of MM, AL, POEMS, and MGUS, and helped identify patient subgroups with specific clinical features.

Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAF^V600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.

Background: A growing body of evidence has shown that circular RNAs (circRNAs) are promising exosomal cancer biomarker candidates. However, global alterations of circRNAs in cancer and the driving force of circRNA biogenesis remain under investigation. Studies on these factors are needed to identify ideal circRNA biomarkers for cancer.Methods: We comparatively analyzed the circRNA landscape in pan-cancer and normal tissues to investigate their biologically significant characteristics and identify circRNAs enriched in pan-cancer. We used co-expression analysis, LASSO regularization, and support vector machine to analyze 265 pan-cancer and 319 normal tissues to identify circRNAs with the highest ability to distinguish cancer tissues from normal tissues which showed high expression in plasma exosomes from patients with cancer (e.g., hepatocellular carcinoma, HCC) and were associated with cancer mutations. Results: Expression of circRNAs was reduced in cancer tissues and plasma exosomes from patients with cancer than in normal tissues and exosomes from healthy controls. The circRNAs with the strongest ability to distinguish between cancer and normal tissues were among the top 10% of stably expressed circRNAs. Compared with normal-tissue-enriched circRNAs, cancer-tissue‒enriched circRNAs exhibited a more prominent association with cancer mutations and higher levels in plasma exosomes from patients with HCC. Particularly, we identified dynein axonemal heavy chain 14 (DNAH14), which serves as the host gene of three cancer tissue-enriched circRNAs, as one of the top back-spliced genes exclusive to cancer tissues. Among these three circRNAs, chr1_224952669_224968874_+ was significantly elevated in plasma exosomes from patients with HCC and was associated with the cancer mutation chr1:224952669: G>A, a splice acceptor variant that is potentially a driving force of circRNA biogenesis.Conclusions: Our bioinformatic analyses provide insights into the characteristics of the circRNA landscape in cancer and the potential of cancer mutation-associated and cancer tissue-enriched RNAs as plasma exosomal cancer biomarkers. Moreover, our results highlight DNAH14 as a host gene that should be further examined in studies of circRNA in cancer.

Although KIAA0101 is involved in many diseases, its expression and prognostic value in HCC remain undefined. According to CCLE, KIAA0101 is highly expressed in HCC, with a weak positive correlation between copy number and gene expression. Four studies involving 760 samples in ONCOMINE report elevated KIAA0101 expression in HCC (p=3.11E-22). The KM plotter revealed high KIAA0101 expression to be associated with worse overall survival in HCC (HR=2.09, p=4.1e-05); this prognostic power was stronger for male than female, early-stage than advanced-stage, and Asian than Caucasian patients. RNA sequencing data for 8 pairs of HCC and adjacent tissue samples validated the significantly high KIAA0101 level (p=0.00497). Moreover, functional annotations of 31 KIAA0101-coexpressed genes show enrichment of terms associated with mitosis, cytoskeleton construction, and chromosome segregation. Among 9 genes having STRING-validated protein-protein interactions with KIAA0101, two are involved in virus-related pathways. Alternative splicing analysis indicated higher expression of variant 1 and variant 2 in HCC and no significant differences in exon usage of KIAA0101 between cancer and normal tissues. These findings support that KIAA0101 is a potential prognostic biomarker for HCC and highlight the association between virus infection and the mechanism underlying the process by which KIAA0101 contributes to poor prognosis of patients.