• Major finding: Stem cells and committed progenitors can both initiate tumors in HOXA9-MEIS1 AML.

  • Concept: HOXA9-MEIS1-induced leu­kemic expansion defies the strict hematopoietic hierarchy.

  • Impact: A specific immunophenotype does not dictate cancer “stemness.”

It remains unclear whether acute myeloid leukemia (AML) is initiated by a specific population of stem cells within a tumor or if cells with a more differentiated phenotype are equally capable of establishing and maintaining the leukemic state. To better understand the nature of tumor-initiating activity, Gibbs and colleagues purified distinct blood cell populations from mice with HOXA9-MEIS1–driven AML and tested their individual ability to initiate disease in secondary recipients. Unexpectedly, cells immunophenotypically resembling hematopoietic stem/progenitor cells as well as committed lymphoid and myeloid progenitors had tumor-initiating activity, and each cell compartment could recapitulate the entire immunophenotypic spectrum of AML following serial transplantation. This observation indicated that the cells with a more differentiated phenotype could give rise to immunophenotypically less differentiated cells or cells of a different lineage, suggesting that HOXA9-MEIS1 induces a dynamic tumorigenic hierarchy that does not adhere to the strict bounds of normal “forward” hematopoiesis. Unsupervised hierarchical clustering of gene expression data revealed that the tumor-initiating cells in HOXA9-MEIS1 primary AML most closely resembled normal hematopoietic stem cells, and a single-cell analysis of tumor-initiating cells using mass cytometry showed that certain common pathways were activated in the distinct tumor-initiating cell populations. The individual tumor-initiating cell populations were also similarly sensitive to inhibition of MEK, DNA methyltransferases, and PI3K in vitro. Inhibition of these shared signaling nodes, but not pathways whose activation varied among the tumor-initiating cell populations, significantly increased survival of HOXA9-MEIS1 AML mice. Although the identification of tumor-initiating cells that establish and maintain hierarchical tumor organization supports the cancer stem cell hypothesis, these findings also suggest that “stemness” in AML can be a phenotypically dynamic, pharmacologically targetable state shared by multiple cell types.

Gibbs KD, Jager A, Crespo O, Goltsev Y, Trejo A, Richard CE, et al. Decoupling of tumor-initiating activity from stable immunotype in Hoxa9-Meis1-driven AML. Cell Stem Cell 2012;10:210–17.

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