Genome-wide analysis unveils the secret of leukemia relapses

by on January 12, 2009 · 0 comments

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Blogging on Peer-Reviewed ResearchAcute lymphoblastic leukemia (ALL) affects people of all ages with a sharp peak of incidence among children ages 2 to 3. After decades of dedicated basic and translational research, the cure rate of ALL is as high as 80%. However, 20% of ALL patients undergo relapse after the initial chemotherapy regimen. What’s wrong? A research group from St. Jude Children’s Research Hospital provides us with new insight into this problem. Charles Mullighan asked what are the clonal origins of relapsed ALL?

Thanks to the emerging modern high throughput methods which provide us a chance to take a full-scale look at the profile of those mysterious liquid tumor cells. Genomic-wide analysis was performed on 242 ALL patients. The results revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases.

The authors asked the next question – how are those genome abnormalities related to the relapse of ALL? What the researchers did was to collect matched pairs of samples from diagnosis and relapse ALL and took a close look at their genomic changes. If you are expecting further evolutionary ALL cells in the relapse samples, you will be disappointed.

What they found was that cells responsible for relapse are ancestral cells to primarily diagnosed ALL in as high as 51% out of 61 patients. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs). Moreover, the CNAs acquired at relapse preferentially affect genes that fall into the category of cell cycle regulation and B cell development.

Clonal relationship of diagnosis and relapse samples in ALL. The majority of relapse cases have a clear relationship to the diagnosis leukemic clone, either arising through the acquisition of additional genetic lesions or, more commonly, arising from an ancestral (prediagnosis) clone. In the latter scenario, the relapse clone acquires new lesions while retaining some but not all of the lesions found in the diagnostic sample. Lesion-specific backtracking studies revealed that in most cases the relapse clone exists as a minor subclone within the diagnostic sample before the initiation of therapy. In only a minority of ALL cases does the relapse clone represent the emergence of a genetically distinct and thus unrelated second leukemia.

(picture credit Charles Mullighan, 2008)

You can definitely ask a bunch of questions stemming from this study. How can we adapt this data to stem cell theory? How can chemotherapy selectively kill target cells? What genes are really necessary for leukemia to manifest? We know the genome abnormality of ALL, we know the difference of diagnosis and relapse ALL, we want to predict. With the same genome-wide analysis on 221 ALL patients, researchers now focus on the deletion of one particular gene – IKAROS as a poor prognosis indicator.

Fortunately, we are working in an era of technology explosion which makes researchers’ dreams true. The only thing of our concern is not to get drown in the “data ocean”.

Charles G. Mullighan is the researcher who completed these studies in three years. Best regards!

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Science 2008;322;5906:1377
N Engl J Med, published online Jan 7, 2009 (10.1056/NEJMoa0808253)

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