Editors' ChoiceAcute Myelogenous Leukemia

Dissecting “Normal” in Leukemia

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Science Translational Medicine  21 Dec 2011:
Vol. 3, Issue 114, pp. 114ec207
DOI: 10.1126/scitranslmed.3003582

The definition of normal can change for many reasons, including advances in technology—and has often done so in medicine. Yi et al. now provide an example of such a change for acute myeloid leukemia (AML), a heterogeneous disorder with different genetic signatures that are associated with variable prognoses. To date, cytogenetic abnormalities—often detected by examining metaphase chromosomes—represent the most reliable pretreatment prognostic factors in adult AML. Normal karyotype (NK) AML (with no visible chromosomal abnormalities) is considered to be of intermediate prognostic risk; NKs are detected in about half of AML patients. Specific mutations, such as FMS-like tyrosine kinase-3 internal tandem duplication (FLT3/ITD), are associated with worse outcomes in NK-AML patients.

Genome-wide single-nucleotide polymorphism (SNP) array–based karyotyping can reveal chromosomal lesions that are not detected by observation of metaphase chromosomes, including copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). Yi et al. examined the bone marrow leukemia cells of 133 patients with a diagnosis of NK-AML. They found that 43 (32.3%) patients had at least one abnormal SNP lesion, with a mean of 2.6 lesions per patient, including 35 CN-LOH lesions. The complete remission rates (74% versus 90%) and 3-year overall survival rates (28% versus 63%) were significantly lower in patients with abnormal SNP lesions than in those without. Patients with abnormal SNP lesions had a significantly shorter survival time (14.2 months) as compared with those without such lesions (80.1 months). In addition to the presence of abnormal SNP lesions, age, AML with antecedent myelodysplastic syndromes, and the FLT3/ITD mutation were confirmed as independent prognostic factors. In patients carrying the FLT3/ITD mutation, however, the detection of SNP lesions was not associated with any additional significant disadvantage for survival. Conversely, in patients without this mutation, detection of SNP lesions was associated with reduced survival time (13.3 months in patients with SNP lesions versus 76.6 months in patients without such lesions).

This result underscores the importance of abnormal SNP lesions as a marker of the accumulation of genetic changes caused by genomic instability in NK-AML. The presence of such lesions can provide insight for the selection of therapeutic strategies, such as early stem cell transplantation. After all, normal cytogenetics may not be all that normal.

J. H. Yi et al., Adverse prognostic impact of abnormal lesions detected by genome-wide single nucleotide polymorphism array–based karyotyping analysis in acute myeloid leukemia with normal karyotype. J. Clin. Oncol. 29, 4702–4708 (2011). [Abstract]

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