A new way to target aggressive blood cancer

Good news! Cancer is history (soon)!

"Researchers ... have found a new way to kill cancer cells of acute myeloid leukemia (AML), one of the most aggressive forms of blood cancer. ...

The new work shows that AML cells require a common molecule called heme to multiply and survive. Without heme, the cancer cells die of a type of cell death called cuproptosis.

“We’ve uncovered a fundamental weakness in AML cells,” ...

“By blocking AML cells from producing heme, we can switch on cuproptosis, a unique form of cell death, and effectively kill the cells most responsible for causing a cancer relapse.”

Cuproptosis is a form of cell death identified in 2022. It involves excessive levels of copper inside cells, which causes oxidative stress and ultimately leads to cell death. ..."

"Highlights

• Heme biosynthesis enzymes are variably suppressed in AML

• Heme levels are linked with altered leukemic transcriptional programs via BACH1

• Heme biosynthesis is a selective dependency in AML, both in vitro and in vivo

• Heme starvation disrupts complex IV, inducing copper accumulation and cuproptosis

Summary

The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML).

The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal.

Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper.

Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis."

A new way to target aggressive blood cancer | News | ConnectSci

Peter Mac researchers uncover new way to target aggressive blood cancer (original news release)

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia

Graphical abstract