2026-07-09 | WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia.

WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström's Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (MYD88MUT) and CXCR4 (CXCR4MUT) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, WNK2 is a top dysregulated gene in MYD88MUT WM. To study WNK2 regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of WNK2 in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in MYD88MUT WM and a novel therapeutic target in hematological and solid tumor oncology.

Open article ↗

2026-07-03 | Diagnostic challenge of occult ER-positive breast carcinoma within bone marrow indolent B-cell lymphoma and response to CDK4/6 inhibitor: a case report.

Bone marrow metastasis from hormone receptor-positive breast cancer can be challenging to detect, especially in patients with concurrent hematologic malignancies, where isolated epithelial cells may be hidden by a dominant lymphoid infiltrate. This situation requires careful histopathologic and immunophenotypic evaluation to prevent misdiagnosis. We report a 74-year-old White woman with Waldenström's macroglobulinemia carrying the MYD88 L265P mutation and bone marrow infiltration by indolent B-cell non-Hodgkin lymphoma. She was evaluated for suspected skeletal disease progression due to rising tumor markers and inconclusive PET findings. Bone marrow biopsy revealed small clusters of epithelial cells positive for estrogen receptor (ER), cytokeratin AE1/AE3, and GATA3, consistent with metastatic breast carcinoma within a lymphoid background. Notably, ER positivity was the only marker indicating epithelial origin. The patient had previously received empirical aromatase inhibitor therapy after the initial detection of scattered ER-positive epithelial cells in 2018. Following disease progression in December 2024, she was treated with palbociclib and fulvestrant, while the indolent lymphoma was managed with active surveillance. At 6-month follow-up, the patient showed clinical stability, a biochemical response, and radiologic evidence of stable disease. This case emphasizes the importance of maintaining a high level of clinical and pathological suspicion when assessing bone marrow infiltration, especially in patients with a history of malignancy. The presence of isolated ER-positive epithelial cells within a lymphoid marrow environment should raise suspicion of occult breast carcinoma metastasis. Due to the rarity of this coexistence, the underlying mechanisms and optimal management strategies are still unclear. To our knowledge, this is one of the few reported cases of occult ER-positive breast carcinoma presenting solely as bone marrow involvement in a patient with indolent B-cell lymphoma, with documented response to CDK4/6 inhibitor-based therapy. This case report was prepared in accordance with the CAse REport (CARE) guidelines.

Open article ↗

2026-06-12 | Waldenström Macroglobulinemia Presenting With Hepatic Lesions: Case Report and Literature Review.

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma characterized by bone marrow (BM) infiltration and monoclonal IgM secretion. Clinical manifestations most often reflect BM involvement, lymphadenopathy, or splenomegaly, while extramedullary disease is uncommon. Hepatic infiltration usually presents as diffuse hepatomegaly; focal hepatic lesions are exceedingly rare, with only two cases previously reported. We describe a 63-year-old woman with a history of celiac disease who presented with fatigue and pancytopenia. Laboratory testing showed elevated IgM with an IgM-λ monoclonal protein. Imaging revealed multiple hypodense hepatic lesions, splenomegaly, and small-volume lymphadenopathy. BM biopsy demonstrated lymphoplasmacytic lymphoma with λ-restricted plasma cells, and molecular studies were negative for MYD88 L265P and CXCR4 mutations. Liver biopsy showed granulomatous inflammation with necrosis, accompanied by IgM-positive, λ-restricted B cells clonally related to the BM infiltrate, consistent with WM involvement. Sarcoidosis and infectious causes were excluded. The patient received six cycles of bendamustine and rituximab (BR), leading to a reduction in hepatic lesions and IgM levels, though treatment was complicated by persistent cytopenias. This case represents the first reported instance of WM presenting with focal hepatic lesions associated with IgM paraproteinemia and a sarcoid-like granulomatous reaction. Recognition of such atypical presentations is essential, as they may mimic primary hepatic lymphoma, sarcoidosis, or infectious granulomatous disease. Comprehensive histopathological and molecular evaluation is critical for accurate diagnosis and appropriate therapy. Our report expands the spectrum of extramedullary WM and highlights the potential for favorable response to BR despite unusual presentation.

Open article ↗