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Molecular genetic demonstration of the diverse evolution of Richter's
syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma)
A Matolcsy, G Inghirami and DM Knowles
Division of Surgical Pathology, Columbia University, College of Physicians
and Surgeons, New York, NY 10032.
Paired samples of chronic lymphocytic leukemia (CLL) or small lymphocytic
lymphoma (SLL) and the subsequent diffuse large cell lymphoma (DLL) of six
cases of Richter's syndrome were investigated to establish the clonal
relationship between the CLL/SLL and the DLL components and to define the
oncogene and/or tumor-suppressor gene alterations involved in the
morphologic transformation of CLL/SLL. Southern blot hybridization analysis
showed identical clonal immunoglobulin (Ig) gene-rearrangement patterns in
the CLL/SLL and DLL components in four cases and different Ig
gene-rearrangement patterns in two cases. Polymerase chain reaction (PCR)
amplification, cloning, and DNA sequencing of complementary determinant
region 3 (CDR3) of the Ig-heavy chain gene of one of the two cases in which
the Ig gene- rearrangement patterns were different showed nonidentical
sequences in the CLL/SLL and DLL components. In the other case, monomorphic
Epstein- Barr virus (EBV) genome integration was detected in the DLL but
not in the CLL, suggesting that the CLL and DLL components in this case of
Richter's syndrome also represent unrelated clones. Single-strand
conformation polymorphism (SSCP) analysis and sequencing of exons 5 through
9 of the p53 tumor-suppressor gene showed a mutation in codon 176 of the
DLL but not in the CLL/SLL component in one case where the CLL/SLL and DLL
represented different clones. The p53 mutation probably played a role in
the development of the lymphoma rather than morphologic transformation of
the CLL/SLL in this case. SSCP analysis and sequencing also showed
identical mutations in codon 282 in both the CLL/SLL and DLL components in
a case where the CLL and DLL represented identical clones. Thus, this p53
gene mutation was present both before and after morphologic transformation,
and therefore, probably did not play a primary role in this process.
Southern blot hybridization analysis failed to show evidence of bcl-1,
bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene
rearrangements in these six cases of Richter's syndrome. In conclusion, the
original CLL/SLL and the subsequent DLL in Richter's syndrome may or may
not be derived from identical clones, and the well-known proto-oncogenes
and tumor- suppressor genes do not appear to play an obvious and consistent
role in the morphologic transformation of CLL/SLL to DLL.
Volume 83,
Issue 5,
pp. 1363-1372,
03/01/1994
Copyright © 1994 by The American Society of Hematology
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