Molecular features responsible for the absence of immunoglobulin heavy chain protein synthesis in an IgH(-) subgroup of multiple myeloma

This study involved 12 patients with multiple myeloma (MM), in whom maligna nt plasma cells did not contain Immunoglobulin heavy chain (IgH) protein ch ains. Southern blot analysis revealed monoallelic J(H) gene rearrangements in 10 patients, biallelic rearrangement in 1 patient, and biallelic deletio n of the J(H) and C-mu regions in 1 patient. Heteroduplex polymerase chain reaction analysis enabled the identification and sequencing of 9 clonal J(H ) gene rearrangements. Only 4 of the joinings were complete V-H-(D)-J(H) re arrangements, including 3 in-frame rearrangements with evidence of somatic hypermutation. Five rearrangements concerned incomplete D-H-J(H) joinings, mainly associated with deletion of the other allele. Curiously, in at least 1 of these 5 cases the second allele seemed to be in germline configuratio n, whereas the inframe V-K-J(K) gene rearrangements contained somatic mutat ions. The configuration of the IGH genes was further investigated by use of C-H probes. In 5 patients the rearrangements in the J(H) and C-H regions w ere not concordant, probably caused by illegitimate IGH class switch recomb ination (chromosomal translocations to 14q32.3). These data indicate that i n many IgH(-) MM patients illegitimate IGH class switch rearrangement or il legitimate deletion of the functional V-H-(D-H)-J(H) allele are responsible for IgH negativity. For example, the exclusive presence of D-H-J(H) rearra ngements in combination with mutated IGK genes can only be explained in ter ms of normal B-cell development, if the second (functional) IGH allele is d eleted, which was probably the case in most patients. Therefore, defects at the DNA level are responsible for the lack of IgH protein production in mo st IgH- MM patients. (C) 2000 by The American Society of Hematology.