Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

By Max Jan, T. Snyder, M. R. Corces-Zimmerman, P. Vyas, Irving L. Weissman, Stephen R. Quake, R. Majeti. Science Translational Medicine, 2012

706 citations recorded by the source corpus.

Exome sequencing and single-cell analysis reveals that a clonal progression of mutations in hematopoietic stem cells precedes human acute myeloid leukemia. Getting to the Root of Acute Myeloid Leukemia Acute myeloid leukemia (AML) is an aggressive clonal malignancy of bone marrow progenitor cells caused by the accumulation of multiple mutations in a single lineage of cells. In the bone marrow, most cells are short-lived and the frequency of mutations is low, making it tough to explain how such a lineage of cells with multiple mutations could arise. In a new study, Jan et al. now propose a model in which AML develops by serial acquisition of mutations in long-lived self-renewing hematopoietic stem cells (HSCs). The authors directly tested their clonal evolution model by sequencing the exomes (the protein-coding regions of the genome) of AML cells and residual HSCs taken from patients with AML. First, they identified the coding mutations present in six AML patient samples by exome sequencing. Then, using cell surface markers to isolate rare residual HSCs by flow cytometry, the researchers discovered leukemia-associated mutations in the HSCs. Finally, the authors performed single-cell assays targeted to the identified mutations to determine the genotype of individual HSCs. They detected multiple cell clones in the HSC pool that contained some, but not all, of the mutations seen in the AML cells. Furthermore, the authors were able to determine the order of acquisition of the mutations that preceded development of AML. These results offer fresh insights into the early stages of AML and pinpoint preleukemic HSCs as an important therapeutic target to prevent relapse and to ensure durable clinical remission after chemotherapy. Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.

Subfields: Cancer Research, Hematology

View Paper: https://www.semanticscholar.org/paper/f90daeb9d832500b0746ce8a6045cb578616d77e

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Citations in the corpus

Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission (2014, methodology): “Targeted Amplicon Sequencing was performed as described previously (22).”
Evolution of the cancer stem cell model. (2014, background): “…that are found in AML blasts, many were actually present in the founder HSC that was the cell of origin for the AML subclone; these mutations arose every time the normal HSC divided and remained functionally neutral and thus can be considered passengers (Jan et al., 2012; Welch et al., 2012).”
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “The TET2 mutations are thought to occur in the early pre-leukemic stage, which contribute to subsequent cancer initiation (Jan et al., 2012).”
Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “First, TET2 mutations can be found in premalignant HSCs in MDS and AML patients and are preserved in the tumor bulk along with additional oncogenic mutations (Jan et al. 2012; Chan and Majeti 2013; Itzykson et al. 2013).”
Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. (2015, methodology): “In the absence of any available intervention to prevent progression, surveillance similar towhat is currently recommended for MGUS could be considered.(4,8,69) In the near term, most individuals who will be screened for somatic mutations will be those with hematologic abnormalities that do not meet ”