The inhibitory receptor Siglec-G controls the severity of chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults in the Western world. B cell receptor (BCR) signaling is known to be crucial for the pathogenesis and maintenance of CLL cells which develop from mature CD5+ B cells. BCR signaling is regulated by the inhibitory co-receptor Siglec-G and Siglec-G-deficient mice have an enlarged CD5+ B1a cell population. Here, we determine how Siglec-G expression influences the severity of CLL. Our results show that Siglec-G deficiency leads to earlier onset and more severe course of the CLL-like disease in the murine Eµ-TCL1 model. In contrast, mice overexpressing Siglec-G on the B cell surface are almost completely protected from developing CLL-like disease. Furthermore, we observe a downmodulation of the human ortholog Siglec-10 from the surface of human CLL cells. These results demonstrate a critical role for Siglec-G in disease progression in mice, and suggest that a similar mechanism for Siglec-10 in human CLL may exist.

Single-Center Experience of Patients with Plasma Cell Leukemia in the Era of New Therapeutics.

INTRODUCTION: Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥5% plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM; however, outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents. METHODS: We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen. RESULTS: Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 (2.0; 22.9) months. All patients were treated with a proteasome-inhibitor (PI)-based induction therapy, and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only 1 patient achieved a remission with daratumumab and subsequent allogenic SCT. CONCLUSION: With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous SCT for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devastating and needs new therapeutic approaches.

CpG stimulation of chronic lymphocytic leukemia cells induces a polarized cell shape and promotes migration in vitro and in vivo.

In order to accomplish their physiological functions leukocytes have the capability to migrate. As a prerequisite they need to adopt a polarized cell shape, forming a leading edge at the front and a uropod at rear pole. In this study we explored the capability of chronic lymphocytic leukaemia (CLL) cells to adopt this leukocyte-specific migration phenotype. Furthermore, we studied the impact of the Toll-like receptor 9 (TLR9) agonists CpGs type A, B and C and the antagonist oligodesoxynucleotide (ODN) INH-18 on the cell polarization and migration process of primary human CLL cells. Upon cultivation, a portion of purified CLL cells adopted polarized cell shapes spontaneously (range 10-38%). Stimulation with CpG ODNs type B (ODN 2006) and CpGs type C (ODN 2395) significantly increased the frequency of morphologically polarized CLL cells, while ODN INH-18 was hardly able to act antagonistically. Like in human hematopoietic stem and progenitor cells, in morphologically polarized CLL cells CXCR4 was redistributed to the leading edge and CD50 to the uropod. Coupled to the increased frequencies of morphologically polarized cells, CpGs type B and C stimulated CLL cells showed higher migration activities in vitro and following intravenous injection higher homing frequencies to the bone marrow of immunocompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Thus, presumably independent of TLR-9 signaling, CpGs type B and C promote the cellular polarization process of CLL cells and their ability to migrate in vitro and in vivo.

Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia.

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.