A model for the molecular pathogenesis of multiple myeloma

Based on the results summarized above, a model for the molecular pathogenesis of MM has been proposed. Chromosome

H cyclin D3

H cyclin D3

Fig. 11.1 Cyclin D expression in normal and malignant plasma cells

The raw scores for each of the three D-cyclins (D1, D2, D3) from the Affymetrix HuFL data set published by Tarte etal. and Zhan et al. are plotted one above the other. The samples are divided into nine groups, and arranged by the level of expression of the predominant cyclin D within each group. The samples are CD138+-selected cells from six peripheral blood-generated plasmablasts and one reactive plasmacytosis (PPC), 31 bone marrow plasma cell (BMPC) from normal volunteers, and 78 samples from patients with newly diagnosed MM and three with plasma cell leukemia. Among these, there are two with high CCND3 (6p21) and 15 with high CCND1 (11 q13); 25 with lower levels of CCND1 without t(11 ;14) (D1); four with lower levels of D1 and elevated CCND2 (D1+D2), 17 remaining patients with elevated CCND2 (D2), and two patients without an elevated cyclin D (D2); nine with elevated FGFR3 (4p16) (4p); seven with elevated CX3CR1 and P7-integrin, a marker of Maf dysregulation (c-maf, 16q23; mafb, 20q11) (maf).

Fig. 11.1 Cyclin D expression in normal and malignant plasma cells

The raw scores for each of the three D-cyclins (D1, D2, D3) from the Affymetrix HuFL data set published by Tarte etal. and Zhan et al. are plotted one above the other. The samples are divided into nine groups, and arranged by the level of expression of the predominant cyclin D within each group. The samples are CD138+-selected cells from six peripheral blood-generated plasmablasts and one reactive plasmacytosis (PPC), 31 bone marrow plasma cell (BMPC) from normal volunteers, and 78 samples from patients with newly diagnosed MM and three with plasma cell leukemia. Among these, there are two with high CCND3 (6p21) and 15 with high CCND1 (11 q13); 25 with lower levels of CCND1 without t(11 ;14) (D1); four with lower levels of D1 and elevated CCND2 (D1+D2), 17 remaining patients with elevated CCND2 (D2), and two patients without an elevated cyclin D (D2); nine with elevated FGFR3 (4p16) (4p); seven with elevated CX3CR1 and P7-integrin, a marker of Maf dysregulation (c-maf, 16q23; mafb, 20q11) (maf).

content appears to identify two different, but perhaps overlapping, pathways of pathogenesis: non-hyperdiploid tumors with a very high incidence of IgH translocations involving the five recurrent partners (above) and a relatively high incidence of chromosome 13/13q14 loss; and hyperdiploid tumors associated with multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19 and 21, but a low incidence of both chromosome 13/13q14 loss and IgH translocations involving the five recurrent partners (Plate 11.1). In about half of the tumors, a primary chromosome translocation results in the dysregulated expression of an oncogene. This may lead directly to cyclin D dysregulation, either directly for cyclin D1 for translocations involving 11q13 or for cyclin D3 for translocations involving 6p21, or indirectly for cyclin D2 translocations involving 4p16, 16q23 and other translocations. Alternatively, the remaining tumors are mostly hyperdiploid, and cyclin D1 (or, less often, cyclin D2) is usually dysregulated by an undefined mechanism. The dysregulation of one of three cyclin D genes may render the cells more susceptible to proliferative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce interleukin 6 (IL-6) and other cytokines. Karyotypic abnormalities, most notably IgH translocations, trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21 and monosomy of chromosome 13 or 13q14 deletion, are often present in premalignant MGUS, the earliest identified stage of tumorigenesis. Even though dysregulation of a cyclin D gene appears to be a nearly universal event in early pathogenesis, there is evidence that the retinoblastoma (Rb) pathway is further disrupted by p16INK4a methyla-tion and inactivation in a substantial fraction of MGUS and MM tumors. Tumor progression is associated with secondary chromosome translocations, of which c-myc provides a paradigm. Mutually exclusive activating mutations of K- or N-Ras [or FGFR3 when there is a t(4;14) translocation] are rare or absent in MGUS, whereas Ras mutations are present in 30-40% of early MM and FGFR3 mutations occur more frequently in advanced MM. Mutations and/or monoallelic deletion of p53 occur frequently but only late in the course of the disease. Further disruption of the Rb pathway by inactiva-tion of Rb or p18INK4c can also occur at a low frequency, most likely as a late progression event. The frequency and timing of other events, such as inactivation of PTEN, remain to be determined.

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