👤 LesleyAnn Hawthorne

Lymphoplasmacytic lymphoma / Waldenström macroglobulinemia (LPL/WM) is a rare and indolent low-grade B-cell lymphoproliferative neoplasm that often presents with vague symptoms or asymptomatically. While it most commonly involves the bone marrow, LPL/WM can sometimes involve the lymph nodes and spleen, and rarely the central nervous system, skin, and pleural cavities. We report a rare case of lymphoplasmacytic lymphoma/ Waldenström macroglobulinaemia presenting with predominant myometrial and cervical involvement. A 57-year-old G2P2 postmenopausal female with a history of HPV + HSIL presented following a single episode of abnormal uterine bleeding with associated urinary urgency and pelvic pressure. Transvaginal ultrasound examination was unremarkable and endometrial biopsy via hysteroscopy was unsuccessful due to stenotic cervical os. The patient subsequently underwent a total robotic hysterectomy with bilateral salpingo-oophorectomy. Examination of histologic sections showed atypical perivascular lymphoid aggregates consistent with involvement by a low-grade B-cell lymphoma with predominant myometrial and cervical involvement. Differential diagnosis at the time included marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). Additional testing identified an IgM kappa paraproteinemia with MYD88 p.L265P mutation. Bone marrow biopsy and aspirate confirmed the diagnosis of lymphoplasmacytic lymphoma / Waldenström macroglobulinaemia (LPL/WM). To our knowledge, there have been only two cases previously described in the literature of LPL/WM involvement in the female genital tract; both of which had prominent involvement of the ovaries. Although exceedingly rare, LPL/WM involvement of the female genital tract should be considered on the differential diagnosis if atypical lymphoid cells or dense lymphoid aggregates are observed. Show less

Myosins are well characterized molecular motors essential for intracellular transport. MYO19 copurifies with mitochondria, and can be released from mitochondrial membranes by high pH buffer, suggesting that positively-charged residues participate in interactions between MYO19 and mitochondria. The MYO19-specific mitochondria outer membrane association (MyMOMA) domain contains approximately 150 amino acids with a pI approximately 9 and is sufficient for localization to the mitochondrial outer membrane. The minimal sequence and specific residues involved in mitochondrial binding have not been identified. To address this, we generated GFP-MyMOMA truncations, establishing the boundaries for truncations based on sequence homology. We identified an 83-amino acid minimal binding region enriched with basic residues (pI ∼ 10.5). We sequentially replaced basic residues in this region with alanine, identifying residues R882 and K883 as essential for mitochondrial localization. Constructs containing the RK882-883AA mutation primarily localized with the endoplasmic reticulum (ER). To determine if ER-associated mutant MyMOMA domain and mitochondria-associated wild type MyMOMA display differences in kinetics of membrane interaction, we paired FRAP analysis with permeabilization activated reduction in fluorescence (PARF) analysis. Mitochondria-bound and ER-bound MYO19 constructs displayed slow dissociation from their target membrane when assayed by PARF; both constructs displayed exchange within their respective organelle networks. However, ER-bound mutant MYO19 displayed more rapid exchange within the ER network than did mitochondria-bound MYO19. Taken together these data indicate that the MyMOMA domain contains strong membrane-binding activity, and membrane targeting is mediated by a specific, basic region of the MYO19 tail with slow dissociation kinetics appropriate for its role(s) in mitochondrial network dynamics. © 2016 Wiley Periodicals, Inc. Show less

Pancreatic endocrine neoplasms (PENs) are rare, mostly well-differentiated endocrine neoplasms, whose biology has been poorly characterized. Global expression microarrays can document abnormal pathways that impact on tumorigenesis and disease progression. RNA was extracted from eight well-differentiated PENs and three highly enriched pancreatic islet cell samples (80-90% purity), and examined using the Affymetrix U133A oligonucleotide microarray. Microarray data were normalized using dCHIP for identification of differentially expressed genes. PEN tissue microarrays were constructed from 53 archival PENs for immunohistochemical validation of microarray data. Sixty-six transcripts were overexpressed > or =3-fold in PENs compared with normal islet cells, including putative oncogenes (MLLT10/AF10), growth factors [insulin-like growth factor-binding protein 3 (IGFBP3)], cell adhesion and migration molecules (fibronectin), and endothelial elements (MUC18/MelCAM and CD31). A total of 119 transcripts were underexpressed < or =3-fold in PENs compared with normal islet cells, including cell cycle checkpoint proteins (p21/Cip1), the MIC2 (CD99) cell surface glycoprotein, putative metastasis suppressor genes (NME3), and junD, a MEN1-regulated transcription factor. Using PEN tissue microarrays, we confirmed the differential up-regulation of IGFBP3 (70%) and fibronectin (22%) and differential down-regulation of p21 (46%) and MIC2 (CD99; 91%) in PENs versus normal pancreatic islets. IGFBP3 overexpression was significantly more common in metastatic (93%) versus primary PEN lesions (60%), P=0.022. Fibronectin overexpression demonstrated a trend toward significance in lymphatic PEN metastases (55%) compared with primary PEN lesions (24%; P=0.14). Global expression analysis provides insight into tumorigenic pathways in PENs and may identify potential prognostic and therapeutic markers for these uncommon neoplasms. Show less