RUNX1 Transcription Factor Maintains Acute Myeloid Leukemia Stem Cells

By Will Boggs MD

June 09, 2020

NEW YORK (Reuters Health) - The RUNX1 transcription factor plays a key role in the maintenance of human acute myeloid leukemia (AML) stem cells (LSCs), researchers report.

"RUNX1 could therefore be an interesting therapeutic target for AML," Dr. Eirini P. Papapetrou of Icahn School of Medicine at Mount Sinai, in New York City, told Reuters Health by email. "However, caution is needed, as reduction of RUNX1 expression in rare cases of individuals with inherited RUNX1 mutations predisposes to AML development (RUNX1-FPD)."

"Thus, RUNX1 may have distinct roles at different stages of leukemogenesis and in different cells (stem cells vs more differentiated cells) and this warrants more nuance in therapeutic approaches targeting this transcription factor," she said.

Dr. Papapetrou and colleagues found that leukemia cells derived through in vitro differentiation of induced pluripotent stem cells (iPSCs) from an AML patient are organized hierarchically and contain cells with hallmark features of leukemia stem cells.

A subpopulation of those induced LSCs, identified by their adherence to plastic, resides at the apex of that hierarchy and is highly enriched for cells with a hematopoietic stem cell immunophenotype and leukemia-initiating potential, the researchers note in Cell Reports.

From these LSCs, the team identified a 16-gene set that correlated with AML patient survival. Within this set, RUNX1 was among the most enriched transcription factors.

In primary AML samples representative of common AML genetic groups, RUNX1 knockdown decreased cell survival and colony formation in most samples, suggesting a role for RUNX1 in the maintenance of primary human AML LSCs across different genetic groups.

Further studies identified 20 genes activated and 47 genes repressed by RUNX1, a gene signature that was significantly enriched in LSC+ cell fractions from AML patients and negatively correlated with patient survival.

TSPAN18, encoding tetraspanin 18, was a prominent mediator of the effects of RUNX1, and overexpression of TSPAN18 partially reversed the effect of RUNX1 knockdown in induced LSCs.

"Taken together, these results characterize a RUNX1-dependent gene program critical for sustaining AML LSCs and nominate TSPAN18 as an important mediator of the RUNX1 effects on AML LSC maintenance," the authors conclude.

"We were at first surprised to find a role for RUNX1 in maintaining AML LSCs, given that RUNX1 has been mostly associated with tumor suppressor roles in AML (the RUNX1 gene harbors loss-of-function mutations in AML, as well as translocations that also seem to abolish its normal function)," Dr. Papapetrou said.

"But after digging further, we found some earlier studies suggesting that RUNX1 expression is a marker of poor prognosis in AML. So, our findings may provide an explanation for this, namely that RUNX1 is required to maintain LSCs and thus propagate the leukemia," she said.

"We likely cannot eradicate AML without eliminating leukemic stem cells, and there is still a lot more to understand about their properties to do this effectively," she added. "New approaches, like the new model we present, could help us illuminate the intricacies of the molecular circuitry of this elusive stem cell so that we can better attack it."

"This new model was used to identify a leukemia stem-cell gene-expression program," co-author Dr. Michael G. Kharas of Memorial Sloan-Kettering Cancer Center, in New York City, told Reuters Health by email. "We plan on testing some of these factors for their requirement in leukemia, which could result in the discovery of new therapeutic targets."

The authors declared no financial interests directly related to the research.

SOURCE: Cell Reports, online June 2, 2020.