Genetic Biomarkers in Acute Myeloid Leukemia

Will the Promise of Improving Treatment Outcomes Be Realized?

Jay Yang; Charles A Schiffer

Disclosures

Expert Rev Hematol. 2012;5(4):395-407. 

In This Article

Five-year View

It is likely that most, if not all, of the relevant genomic abnormalities in AML will be identified in the next few years as whole genome sequencing of more patients is accomplished. Indeed, this may have already occurred. The difficulty in capitalizing on these findings remains the same as it has been for decades. Stated differently, the challenge is not the molecular biology, but rather further dissection of the chemistry/biochemistry of the pathways affected by these mutations or gene over- or under-expression, thereby allowing inhibition (or stimulation) of the pathway as the case may require.

As the cost and time to completion of whole-genome sequencing decrease, it will eventually become practical to sequence the entire AML genome from an individual patient rather than to screen for a multitude of mutations.[115] There is, however, an important difference between prognostication and improved therapy before the promise of so-called personalized medicine will become a reality.

The application of next-generation sequencing to detect cryptic translocations may have more immediate therapeutic implications. Recently a report describing the use of next-generation sequencing to uncover a cryptic t(15;17) led to the successful use of targeted therapy (arsenic trioxide) in an individual patient.[116] In this case, whole-genome sequencing was accomplished in 7 weeks. Sequencing of the AML genome at diagnosis and at relapse has also confirmed that different clones of the leukemic blast population exist within the same patient at the time of diagnosis.[117] Clinical relapse may be due to either persistence of the original dominant clone or growth of a minority subclone that has gained additional mutations. This presents both a challenge and an immense opportunity to target different clones at different time points in the course of disease. The interpersonal heterogeneity of cancer is now well recognized, but the intrapersonal and even intratumoral heterogeneity will increasingly be a focus of continued investigation.[118,119]

The future of AML therapy can be rationally viewed with either a healthy dose of skepticism or with a Pollyana-like optimism. The truth will probably be somewhere in between. Although the discovery of new mutations and their prognostic implications have been stunning, a better understanding of the molecular underpinnings of AML will be necessary to formulate discrete hypotheses that will drive the development of rationally designed therapies. Progress in drug therapy will probably be much more gradual than the current rapidly evolving discovery phase. The importance of putting patients in appropriately designed clinical trials to test these hypotheses cannot be overemphasized.

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