The assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the Ile 122 allele.

IntroductionChronic lymphocytic leukemia (CLL) is characterized by the abnormal expansion of cells in a CD5 ϩ (B-1) cell clone. 1,2 In this distinctive form of leukemia, most of the malignant cells are in the G 0 /G 1 phase of the cell cycle. 3,4 Disease results from the progressive accumulation of tumor cells which do not proliferate rapidly, but fail to undergo death. 5 In this regard, CLL provides a paradigm for studies of apoptosis inhibition in lymphocytes. In contrast to other B-cell neoplasms such as follicular lymphoma, Burkitt lymphoma, and mantle cell lymphoma that are characterized by specific cytogenetic abnormalities and dysregulated oncogenes, CLL is not distinguished by a common genetic defect. 6 Rather, the diagnosis of CLL is determined by the morphologic and phenotypic properties of the slowly dividing B cells.Despite their prolonged survival in vivo, most CLL cells do not survive for more than a few days in vitro. A longstanding puzzle for investigators is the propensity of CLL B cells to undergo spontaneous apoptosis in culture. Several lines of evidence support that nonmalignant cells and other host elements extrinsic to CLL cells provide survival signals to the tumor cells in vivo. These factors would include bone marrow stromal cells, 7 immune complexes in the context of accessory leukocytes, 8 "nurse-like" cells, 9 and soluble cytokines such as interleukin 4 (IL-4) 10 and tumor necrosis factor alpha (TNF␣). 11,12 On the basis of observations that CD40 ligation in CLL B cells is a powerful stimulus to induction of NF-B 13,14 and survival, [13][14][15][16] we have proposed that CLL tumor growth in vivo would be promoted by inflammatory elements such as CD40 ligand (CD154), cytokines, and antigens to which the tumor cells bind. 4,17 Like nonmalignant B-1 cells, CLL cells usually express surface IgM (sIgM) with the capacity to bind multiple infectious and autologous structures. [18][19][20][21] In the murine system it is established that the presence of autologous antigens for which the B-cell receptor (BCR) has affinity can positively influence nonmalignant CD5 ϩ B-cell fate and differentiation. 22 An emerging body of literature indicates CLL tumor cells often bear mutated Ig gene sequences, [23][24][25] suggesting that the cells have interacted with antigens in vivo. However, the intracellular signaling pathways by which antigens mediate survival in murine and human B-1 cells, and in leukemic B cells, are largely unknown.The purpose of this study was to determine how sIgM engagement affects CLL cell survival, and to identify key molecular components of an antigen-receptor-driven survival program in the leukemic cells. Here, using freshly isolated cells from more than 20 patients with CLL, we determined that BCR crosslinking favors survival in a process characterized by caspase inhibition, induction of NF-B, and expression of antiapoptotic molecules including bcl-2, mcl-1, and bfl-1. The antiapoptotic effects of sIgM engagement in CLL cells were magnified when CD40 was also engaged, and were...

The transthyretin (TTR) Ile 122 variant is associated with cardiac amyloidosis in individuals of African descent. To determine the prevalence of the allele encoding TTR Ile 122 in African-Americans, we have used PCR and restriction analysis to test DNA from African-Americans from various geographic areas, and found an allele frequency of 66/3376 (0.020), which is higher than the value we previously reported in a much smaller pilot study. Our data indicate that this TTR variant is present at equal frequency in African-Americans throughout the U.S., and suggest that this mutation may be a common, often unrecognized cause of cardiac disease in African-Americans.