During the last decade, the improvement of our understanding of the molecular basis of cancer has led to better diagnosis and prognosis for several types of cancer of the hematopoietic system or leukemias, as exemplified by the development of Gleevec (the commercial name of Imatinib), a drug successfully used in the treatment of acute myeloid leukemia (AML). Despite these and several other advances in cancer molecular medicine, there is no effective treatment in the event of cancer relapse and these patients have very poor prognosis. It is generally argued that relapsed leukemia is comprised of clones that display an enhanced resistance to the treatment, yet a formal comparison between the original tumors and the relapsed ones has not been performed.
In a recent issue of Science, Mullighan et al. address this problem and shed new lights on the underlying genetic basis of relapse in pediatric acute lymphoid leukemia (ALL).
By using SNP microarrays, they performed genome-wide DNA copy number analyses and compared relapsed tumors with their original counterparts (i.e. the tumor at the time of diagnosis). The samples typically showed different patterns of copy number alterations (CNAs).
By means of this genome-wide strategy, the authors were also able to validate several loci already suggested to be involved in the relapse of this disease. Besides unveiling genetic differences between the main leukemia population at the time of diagnosis and the relapsed one, they were also able to trace the origin of the latter by comparing the CNAs of the relapsed leukemia with the ones present in the leukemia at the time of diagnosis.
The logic behind this can be illustrated through an example: imagine that a relapsing leukemia lacks a chromosomal amplification that was present in the main population of cancer cells in the original tumor. This suggests that the relapsing leukemia comes from either a rare therapy-resistant clone originally present as a small subpopulation at the time of diagnosis, or it is a new leukemia altogether. If enough loci are assessed, then a “genomic-signature” (presence/absence of amplifications in determined loci) can be used as an identity tag on each leukemic clone, and from these, derive the evolutionary relationships between the different populations of tumor cells from both samples. In other words, you will be able to infer, with confidence, if the clones present in the relapse are derived from the original leukemia populations (either the main or subpopulations) or are indeed, new tumors.
Their analysis shows that 6% of relapsing leukemias are genetically distinct (i.e. possible independent tumors), 8% share the same genetic profile than the initial disease, 34% show clonal evolution from the original clone (i.e. have all the features of the initial clone, plus unique new ones), and 52% percent of the relapsed leukemias are comprised of ancestral clones that initially represented only a minor subpopulation in the original tumor.
It then appears that the majority of relapsing tumors in this disease are actually derived from a rare clone in the original tumor, further supporting the generalized notion that clinical intervention selects different subsets of cells within a heterogeneous tumor and favoring the concept of therapeutic intervention as a shaping force in the enrichment of subpopulations within a tumor. It is noteworthy that not all tumors may behave this way and it remains unclear whether these findings may be applicable to solid tumors.
Interestingly, when analyzing the genetic alterations present in the relapsed disease, no regions comprising drug resistance genes seemed to differ from their original counterparts. Provocatively, most of the alterations were present in genes involved in cell cycle regulation and B-cell development. These results challenge the view held for other leukemias, such as AML, where several studies show that relapsed diseases are comprised of drug-resistant clones.
Although there are particular known differences between “original” tumors and their relapsing counterparts, this study constitutes the first one to study genetic differences at a genome-wide level in the setting of pediatric leukemia. Their findings give new insights into the mechanisms that drive a tumor´s resistance to current therapeutic approaches and cast light onto new potential targets that could be exploited to tip the scale in favor of the relapsing patient.
The authors conclude:
In a recent issue of Science, Mullighan et al. address this problem and shed new lights on the underlying genetic basis of relapse in pediatric acute lymphoid leukemia (ALL).
By using SNP microarrays, they performed genome-wide DNA copy number analyses and compared relapsed tumors with their original counterparts (i.e. the tumor at the time of diagnosis). The samples typically showed different patterns of copy number alterations (CNAs).
By means of this genome-wide strategy, the authors were also able to validate several loci already suggested to be involved in the relapse of this disease. Besides unveiling genetic differences between the main leukemia population at the time of diagnosis and the relapsed one, they were also able to trace the origin of the latter by comparing the CNAs of the relapsed leukemia with the ones present in the leukemia at the time of diagnosis.
The logic behind this can be illustrated through an example: imagine that a relapsing leukemia lacks a chromosomal amplification that was present in the main population of cancer cells in the original tumor. This suggests that the relapsing leukemia comes from either a rare therapy-resistant clone originally present as a small subpopulation at the time of diagnosis, or it is a new leukemia altogether. If enough loci are assessed, then a “genomic-signature” (presence/absence of amplifications in determined loci) can be used as an identity tag on each leukemic clone, and from these, derive the evolutionary relationships between the different populations of tumor cells from both samples. In other words, you will be able to infer, with confidence, if the clones present in the relapse are derived from the original leukemia populations (either the main or subpopulations) or are indeed, new tumors.
Their analysis shows that 6% of relapsing leukemias are genetically distinct (i.e. possible independent tumors), 8% share the same genetic profile than the initial disease, 34% show clonal evolution from the original clone (i.e. have all the features of the initial clone, plus unique new ones), and 52% percent of the relapsed leukemias are comprised of ancestral clones that initially represented only a minor subpopulation in the original tumor.
It then appears that the majority of relapsing tumors in this disease are actually derived from a rare clone in the original tumor, further supporting the generalized notion that clinical intervention selects different subsets of cells within a heterogeneous tumor and favoring the concept of therapeutic intervention as a shaping force in the enrichment of subpopulations within a tumor. It is noteworthy that not all tumors may behave this way and it remains unclear whether these findings may be applicable to solid tumors.
Interestingly, when analyzing the genetic alterations present in the relapsed disease, no regions comprising drug resistance genes seemed to differ from their original counterparts. Provocatively, most of the alterations were present in genes involved in cell cycle regulation and B-cell development. These results challenge the view held for other leukemias, such as AML, where several studies show that relapsed diseases are comprised of drug-resistant clones.
Although there are particular known differences between “original” tumors and their relapsing counterparts, this study constitutes the first one to study genetic differences at a genome-wide level in the setting of pediatric leukemia. Their findings give new insights into the mechanisms that drive a tumor´s resistance to current therapeutic approaches and cast light onto new potential targets that could be exploited to tip the scale in favor of the relapsing patient.
The authors conclude:
"The diversity of genes that are targeted by relapse-associated CNAs, coupled with the presence of the relapse clone as a minor subpopulation at diagnosis that escapes drug-induced killing, represent formidable challenges to the development of effective therapy for relapsed ALL. Nonetheless, our study has identified several common pathways that may contain rational targets against which novel therapeutics agents can be developed".
Here's the abstract and reference:
Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia.
Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, Downing JR.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 pediatric patients with ALL. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs), with the CNAs acquired at relapse preferentially affecting genes implicated in cell cycle regulation and B cell development. Most relapse samples lacked some of the CNAs present at diagnosis, which suggests that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies revealed that cells corresponding to the relapse clone were often present as minor subpopulations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment, and they point to new targets for therapeutic intervention.
C. G. Mullighan, L. A. Phillips, X. Su, J. Ma, C. B. Miller, S. A. Shurtleff, J. R. Downing (2008). Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia Science, 322 (5906), 1377-1380 DOI: 10.1126/science.1164266
1 Comment:
While reviewing this post before we published it, I mentioned to Francisco that there was a phrase in the article's abstract I felt was a little presumptuous:“These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment”.
Here's my comment on that phrase, I attached as part of my reviewing comments to Pancho's analysis of the article:
Cancer cells are abnormal per se. It is important to keep in mind (or at least this is how I think about it) that just because the relapse population has certain differing genomic copy number abnormalities from the original main population (which could be just one of the many ways these populations differ from their original ones), it does not imply causality, or, in other words, there's not way you can know (or argue) that the differing abnormalities are indeed the cause of, or are even related to, the relapse.
So, I think that saying that “the genomic abnormalities contribute to the relapse”, is to the very least an unsupported idea.
Despite this, it is still interesting to notice that many of the CNAs were present in genes involved in cell cycle regulation and B-cell development
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