Waldenström's Macroglobulinemia (WM) is a rare, indolent, non-Hodgkin's lymphoma whose molecular pathology remains poorly understood. This disease is characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow, and is often histopathologically indistinguishable from marginal zone lymphoma, IgM-secreting myeloma, and chronic lymphocytic leukemia with plasmacytic differentiation. To better understand the genomic landscape of this disease, whole genome sequencing was performed on bone marrow samples from thirty WM patients, ten of which were paired with germline tissue. This study identified two genes that are frequently mutated in WM: MYD88 and CXCR4. MYD88 was somatically mutated in 90% of WM samples, which displayed a single nucleotide variant resulting in a leucine to proline substitution at position 265. As prev iously demonstrated in activated B-cell subtype of diffuse large B-cell lymphoma, this mutation results in constitutive activation of the Toll-like receptor pathway and activation of nuclear factor kappa B (NF𝜅B). Highly sensitive allele specific polymerase chain reaction assays were developed to detect MYD88L265P in WM and related hematological malignancies. These studies demonstrated that MYD88L265P could be used to aid in the differential diagnosis, response assessment, and detection of minimal residual disease in WM. Moreover, MYD88L265P was observed in 50% of the precursor condition, IgM monoclonal gammopathy of undetermined significance, suggesting that it is an early event in the pathogenesis of WM. Blocking MYD88 dimerization or the use of downstream IRAK1/4 kinase inhibitors decreased the phosphorylation and nuclear localization of NF𝜅B. Somatic mutations in CXCR4 were only found in the regulatory C-terminal tail and were present in 29% of WM patients. These mutations were similar or identical to those found in the germline of patients with the autosomal dominant disease Warts, Hypogammaglobulinemia, Infection, and Myelokathexis (WHIM) syndrome. CXCR4 somatic WHIM-like mutations were found nearly exclusively in MYD88L265P mutated patients. These mutations impaired receptor internalization, increased signaling downstream of CXCR4, and instilled resistance to several WM directed therapeutics. WM patients who were wild type for both CXCR4 and MYD88 demonstrated inferior overall survival. These studies evidence highly recurring somatic events, and provide a genomic basis for the molecular pathogenesis of WM.

© 2017, © 2017 American Federation for Medical Research. A middle-aged man presents with acute pancreatitis of unknown etiology and is found to have a presentation consistent with the diagnosis of type 2 autoimmune pancreatitis (AIP). AIP is a group of rare heterogeneous diseases that are challenging to diagnose. There are 2 types of AIP. Type 1 disease is the more common worldwide than type 2 AIP. While type 1 AIP is associated with IgG4-positive antibodies, type 2 AIP is IgG4 antibody negative. Both types of AIP are responsive to corticosteroid treatment. Although type 1 AIP has more extrapancreatic manifestations and more commonly relapses, this is a case of a patient with type 2 AIP with inflammatory bowel disease and relapsing course.

<p>B cell lymphomas and leukemias are heterogeneous tumors with different cellular origins. Analysis of immunoglobulin (Ig) genes enables insight into the B cell progenitor, as Ig somatic hypermutation correlates with antigen-related B cell transit through the germinal center (GC). Also, restricted Ig variable heavy chain (V_H) gene repertoires in B cell malignancies could imply antigen selection during tumorigenesis. The length of telomeres has been shown to differ between GC B cells and pre/post-GC B cells, possibly representing an alternative angle to investigate B cell tumor origin. </p><p>Mantle cell lymphoma (MCL), previously postulated to derive from a naïve, pre-GC B cell, was shown to have an Ig-mutated subset (18/110 MCLs, 16%), suggestive of divergent cellular origin and GC exposure. Another subset of MCL (16/110, 15%), characterized by V_H3-21/V_λ3-19 gene usage, alludes to a role for antigen(s) in pathogenesis, also possible for hairy cell leukemia (HCL) in which the V_H3-30 gene (6/32, 19%) was overused. HCL consisted mainly of Ig-mutated cases (27/32, 84%) with low level intraclonal heterogeneity, contrasting with the proposed post-GC origin, for both Ig-mutated and Ig-unmutated HCLs. For MCL and HCL, derivation from naïve or memory marginal zone B cells which may acquire mutations without GC transit are tempting speculations, but currently little is known about this alternative immunological pathway. Heavily mutated Ig genes without intraclonal heterogeneity were demonstrated in lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (13/14, 93%), confirming that the precursor cell was transformed after GC affinity maturation. Telomere length analysis within 304 B cell tumors revealed variable lengths; shortest in the Ig-unmutated subset of chronic lymphocytic leukemia, longest in the GC-like subtype of diffuse large B cell lymphoma, and homogeneous in MCL regardless of Ig mutation status. However, telomere length is complex with regard to GC-related origin.</p><p>In summary, this thesis has provided grounds for speculation that antigens play a role in MCL and HCL pathogenesis, although the potential antigens involved are currently unknown. It has also enabled a more informed postulation about the cellular origin of B cell tumors, which will ultimately enhance understanding of the biological background of the diseases. </p>

B cell lymphomas and leukemias are heterogeneous tumors with different cellular origins. Analysis of immunoglobulin (Ig) genes enables insight into the B cell progenitor, as Ig somatic hypermutation correlates with antigen-related B cell transit through the germinal center (GC). Also, restricted Ig variable heavy chain (VH) gene repertoires in B cell malignancies could imply antigen selection during tumorigenesis. The length of telomeres has been shown to differ between GC B cells and pre/post-GC B cells, possibly representing an alternative angle to investigate B cell tumor origin. Mantle cell lymphoma (MCL), previously postulated to derive from a naïve, pre-GC B cell, was shown to have an Ig-mutated subset (18/110 MCLs, 16%), suggestive of divergent cellular origin and GC exposure. Another subset of MCL (16/110, 15%), characterized by VH3-21/Vλ3-19 gene usage, alludes to a role for antigen(s) in pathogenesis, also possible for hairy cell leukemia (HCL) in which the VH3-30 gene (6/32, 19%) was overused. HCL consisted mainly of Ig-mutated cases (27/32, 84%) with low level intraclonal heterogeneity, contrasting with the proposed post-GC origin, for both Ig-mutated and Ig-unmutated HCLs. For MCL and HCL, derivation from naïve or memory marginal zone B cells which may acquire mutations without GC transit are tempting speculations, but currently little is known about this alternative immunological pathway. Heavily mutated Ig genes without intraclonal heterogeneity were demonstrated in lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (13/14, 93%), confirming that the precursor cell was transformed after GC affinity maturation. Telomere length analysis within 304 B cell tumors revealed variable lengths; shortest in the Ig-unmutated subset of chronic lymphocytic leukemia, longest in the GC-like subtype of diffuse large B cell lymphoma, and homogeneous in MCL regardless of Ig mutation status. However, telomere length is complex with regard to GC-related origin. In summary, this thesis has provided grounds for speculation that antigens play a role in MCL and HCL pathogenesis, although the potential antigens involved are currently unknown. It has also enabled a more informed postulation about the cellular origin of B cell tumors, which will ultimately enhance understanding of the biological background of the diseases.