Acute myeloid leukemia (AML) arises from "founding clones" of cells that cause myelodysplastic syndromes (MDS), suggesting that targeted therapies should be directed at mutations in the original clones, investigators reported.
Paired bone marrow samples revealed 85% clonality between MDS and AML cells of patients who had MDS and subsequently developed fatal AML. The AML samples contained mutations in 11 recurrently mutated genes, four of which had not previously been implicated in MDS or AML, as reported online in the New England Journal of Medicine.
"In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations," Timothy Graubert, MD, of Washington University in St. Louis, and co-authors wrote. "All founding clones and subclones contained at least one mutation in a coding gene."
The results suggest that the evolution of AML "is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection," they added. "Recurrent gene mutations are found in both founding clones and daughter subclones."
The findings provide new insights into the malignant potential of MDS and have the potential to reshape the conceptual framework of therapy for AML.
Investigations of MDS and AML have shown that the two conditions overlap with respect to the cytogenetic and molecular lesions associated with the conditions.
Nonetheless, the fact that most cases of MDS do not progress to AML has created confusion about the status of MDS as a form of cancer, according to the background of the article.
Extensive investigation of both conditions has failed to yield much information about the genetic progression of MDS to AML. Graubert and colleagues performed whole-genome sequencing of bone marrow samples from seven patients with AML and compared the findings with those of samples obtained from the same patients prior to progression from MDS to AML.
Diagnosis of MDS requires a finding of <20% myeloblasts in bone marrow. However, some evidence has suggested that the clonal population of cells in MDS can exceed 20%, the authors noted in the description of their methods.
Using capture sequencing data, the investigators accurately measured clonal cells in MDS samples, calculated mutant allele frequencies for all validated point mutations, and performed cluster analysis.
Each MDS and AML sample contained a founding clone of cells, defined as the mutation cluster (containing 182 of 660 somatic mutations) with the highest mutant allele burden.
"In all cases, the majority of unfractionated bone marrow cells ... in the myelodysplastic-syndrome samples were clonal and indistinguishable from the cells in the secondary-AML samples, even with a myeloblast count of less than 5%," Graubert and co-authors wrote.
"Although these results confirm previous observations that the myeloblast count can underestimate the size of the clonal population in MDS, they also suggest that when the entire genome is interrogated for mutations, clonal hematopoiesis involving most of the bone marrow appears to be the rule, even in early-stage MDS."
The mutations that drive clonal outgrowth at each stage of progression from MDS through AML are not known. However, the founding clone in the seven MDS samples persisted in the seven AML samples and included at least one tier 1 mutation. The founding clones acquired at least one new tier 1 mutation during the generation of AML-specific clusters, the authors wrote.
Therapies that target late-occurring mutations in AML likely will have no effect on early mutations in founding clones.
"It's probably not enough to know that a particular mutation exists in cancer cells," Graubert said in a statement. "We likely will need to dig deeper to find out whether a mutation is in the founding clone that initiated the cancer, or in a later-evolving clone."
"To kill a tree, you have to pull out the roots," he added. "If you only cut off a limb, it will just grow back. We're saying that to be effective, targeted cancer drugs probably need to attack mutations at the root of this disease."
The study was supported by the National Institutes of Health.
The authors had no relevant disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
New England Journal of MedicineSource Reference: Walter MJ, et al "Clonal architecture of secondary acute myeloid leukemia" N Engl J Med. 2012; DOI:10.1056/NEJMoa1106968.