Jumping translocations and high-risk myeloma

In this issue of Blood, Sawyer et al show that jumping translocations of chromosome 1q constitute a mechanism by which widespread damage to the myeloma genome can occur, driving the progression of standard to high-risk clinical behavior.¹  The description of this type of disease-specific mechanism pushing disease forward is an important step forward in understanding the biology of myeloma, because although we understand many of the genetic lesions present in myeloma, we have little insight into the mechanisms that cause them, especially those responsible for disease progression.

With the application of global genetic technologies to characterize the myeloma genome, we are beginning to define the genetic lesions that transform a normal plasma cell into a cell with the features of a myeloma-propagating cell (MPC). This cell initiates the myeloma clone and subsequently evolves, leading to the monoclonal gammopathy of undetermined significance, smouldering multiple myeloma and multiple myeloma.²  Importantly, when we consider how these lesions interact to drive this process forward, a simplistic reductionist approach is to consider them as either initiating or progression events that sustain the evolution of the clone once it has been established.

In myeloma, the known initiating lesions include chromosomal translocations into the Ig gene loci, mediated by a mechanism involving predominantly abnormal class-switch recombination but also involving receptor revision and possibly VDJ recombination.³  The other large subgroup of myeloma is initiated by the gain of whole chromosomes, the so-called hyperdiploid group, but little is known of the exact mechanism by which this arises.

Subsequent to its initiation, the progression of myeloma is driven via the acquisition of genetic lesions, which collaborate with the initiating event to improve the survival and genetic diversity of the MPCs, which subsequently come to clonally dominate the myeloma survival niches according to Darwinian principles.^4,5  The full spectrum of these genetic events, the order in which they occur, and collaborating combinations is not well defined.⁶  However, we know that the genetic lesions are either activated or inactivated by a number of molecular mechanisms, including interstitial copy number gain, activating mutation, chromosomal translocation, or via loss of copy number or inactivating mutation. The full extent of copy-number gains, losses, and mutational spectrum of myeloma has been extensively reported recently.⁷  Of these lesions, the most important clinically are the t(4;14) 1q+ and 17p−, all of which are associated with adverse clinical outcomes. Interestingly, these lesions tend to occur together more than would be expected by chance, and in this situation they have a worse clinical outcome.⁸ 

Despite these recent successes in describing the genetics of myeloma, we have little if any idea of the causative mechanisms leading to their formation. Such mechanisms could either be random, with the cells carrying them coming to dominate because of the selective advantage they confer, or alternatively there could be specific and recurrent genetic mechanisms leading to the deregulation of a set of collaborating genes giving rise to aggressive clinical behavior. An answer to this important question would represent a significant step forward in our attempts to predict clinical outcome and could also open the way to specific clinical interventions. Interestingly, there are 2 loci where this question could be specifically addressed. The first example is MYC, a critical myeloma oncogene located at 8q24. We know that MYC is deregulated by mechanisms involving translocation both to the Ig locus and to superenhancers at other sites.⁹  The other locus where mechanistic insights may be gained is chromosome 1q, which is the most frequently gained chromosomal locus in myeloma (40%) and has an important negative impact on prognosis. Interestingly, until now the biological impact, the relevant deregulated gene, and the mechanism underlying the gain of copy number was unknown.

The authors have published previously on the importance of jumping translocations at 1q12, designated as JT1q12, which is potentially the result of hypermethylation of the 1q12 pericentromeric heterochromatin. This region is special because it is the largest single block of late-replicating highly replicating satellite II/III DNA, which is known to contain unstable segmental duplications that could underlie the development of jumping translocations into this region.

Although this region can be amplified directly leading to 1q+, in addition it can be translocated into a number of receptor chromosomal regions. These translocations lead to gain of 1q, located on the receptor chromosome, but can also lead to loss of genetic material, potentially leading to the deregulation of genes at the receptor site. They show that this mechanism can deregulate MYC, BCL2, FGFr3, CYLD, and WWOX, all of which are genes relevant to the myeloma. They also define an important new mechanism based on JT1q12 whereby multiple regions of the genome can be deregulated by a single mechanism. The new pathologic mechanism involves sequential translocations of the JT1q12 from one receptor chromosome to another, which at the same time leads to amplification of regions from the original receptor chromosome, which become part of the second translocation. Thus, it appears that these jumping translocations can lead to both amplification and deletions of interstitial chromosomal regions throughout the genome. This mechanism, when combined with the Darwinian outgrowth of subclones, with a growth advantage, based on deregulation of myeloma specific genes, could lead to progression via a myeloma-specific mechanism. In this respect, they also go on to define a specific association of JT1q12 with 17p−, the site of the P53 gene, an important negative prognostic factor in myeloma. Extending this observation further, they describe in 6 of 14 patients with t(4;14) the role of JT1q12 as a mechanism leading to 17p−. This observation implicates a specific mechanism driven via JT1q12, active in t(4; 4) myeloma, which mediates rapid progression of the disease from standard to high-risk disease. Using this mechanism as an example, they also confirm the importance of clonal selection leading to clonal predominance as being the mechanism underlying disease progression.