P53 deletion is not a frequent event in multiple myeloma

Abstract

Summary. Recently a high incidence of interstitial deletion of the P53 locus has been reported in multiple myeloma (MM) patients. Considering the importance of such an event, we analysed 79 patients with advanced-stage disease usinḡ uorescence in situ hybridization (FISH). Strikingly, we found only 7/79 patients with a P53 deletion. In order to rule out any differences in probe selection, we reanalysed all the patients with the same probe as that used in a previous study, and con®rmed the low incidence of P53 deletion (7/79, 9%).The only explanation is a difference in hybridization ef®ciency. Since hybridization is far less ef®cient on malignant plasma cells than on other bone marrow cells we suggest that this poor hybridization ef®ciency may lead to a false P53 deletion.

Selective Pharmacologic Activation of the p53-Dependent Pathway as a Therapeutic Strategy for Hematologic Malignancies

“…These analyses are in good agreement with genetic and cytogenetic studies, that generally imply p53 defects in about 10% of medullary myeloma cases, but report higher incidences for patients with plasma cell leukemia. [17][18][19][20] Our observations confirm the target specificity of nutlin-3a and clearly demonstrate the p53 dependence of the observed biological effects. These experiments suggest that the downstream components of the p53 pathway appear to be at least partially intact in more than 90% of primary medullary MM cases.…”

Chromosome translocations in multiple myeloma

“…The karyotypic abnormalities often, but not always, juxtapose c-myc and an Ig enhancer, with 9/25 (36%) of MM cell lines and 8/17 (47%) of primary tumors having a karyotypic abnormality of c-myc that does not involve an apparent association with an Ig enhancer. By interphase FISH analyses, it is reported that c-myc is associated with the IgH locus in 3/140 MM tumors representing all stages, and in none of 79 MGUS tumors (Avet-Loiseau et al, 1999b). Cloned t(8;14) translocation/insertion breakpoints often do not occur at the IgH sites targeted by the three B cell speci®c DNA modi®cations.…”

“…Interphase FISH analyses using probes that¯ank an Ig locus to detect split signals or a probe from one end of an Ig locus together with a probe from a speci®c chromosomal region to detect fusion signals permit a comprehensive assessment of Ig translocations in all tumor cells, including MGUS. To minimize the signi®cant background problems with interphase FISH assays, tumor cells have been enriched by pre-selection (e.g., CD-138 magnetic bead selection), or by restricting analysis to cells that express cytoplasmic kappa or lambda IgL (Ahmann et al, 1998;Avet-Loiseau et al, 1999b).…”

“…This IgL analysis included the three cell lines lacking an IgH translocation, and all three had Igl translocations, so that all 39 lines analysed have either an IgH or Igl translocation. By interphase FISH analyses (Avet-Loiseau et al, 1999b, 1999cNishida et al, 1997), it was reported that IgH translocations are present in 36/79 (47%) of MGUS tumors, in approximately 60% of patients with intramedullary MM, and in 70 ± 80% of patients with primary or secondary PCL. Two di erent IgH translocations were identi®ed in 3/40 (8%) PCL tumors, but in less than 1% of intramedullary MM tumors.…”

An update on molecular biology and drug resistance mechanisms of multiple myeloma

“…p53 is inactivated in 10-12% of MM cases (Avet-Loiseau et al, 1999;Chng et al, 2007) resulting from either p53-DNA binding domain mutations or overexpression of murine double minute 2 gene (MDM2) (Farnebo et al, 2010). MDM2, an E3-ubiquitin ligase, binds p53 to ubiquitinate and targets it for degradation through ubiquitin/proteasome pathway (Piette et al, 1997).…”