Ninety-five percent of all patients with chronic myeloid leukemia (CML) carry a Frankenstein-like gene called BCR-ABL, created from an abnormal fusion of two genes normally found on two separate chromosomes. Like a water faucet without a shutoff valve, the resulting mutant protein stays in the “on” position, leading to uncontrolled cell division and eventually to CML and other blood cancers.
Cancer drug
Gleevec, a revolutionary, targeted cancer drug that specifically blocks the BCR-ABL protein, was approved by the FDA in 2001 and doubled 5-year survival rates for CML patients (31 to 59%) over that decade.
Still, some patients who are responsive to the Gleevec class of drugs become resistant to the treatment and suffer a relapse. Until now, research studies have pointed to an accumulation of additional DNA mutations as the driving force behind cancer cell rebound.
CIRM-funded study
But on Monday, a CIRM-funded UC San Diego team reported in PNAS that reducing just one protein. That protein, MBNL3, activates a cascade of genes in CML cancer cells normally responsible for the unlimited self-renewing capacity of embryonic stem cells.
Much like researchers can reprogram a skin cell back into an embryonic-like state using induced pluripotent stem cells (iPSCs), this suggests they could do that with CML. This approach may help it spread by exploiting the same cellular reprogramming machinery.
Blast cells
CML is a slowly progressing cancer that initially begins with a chronic phase. At this stage, cancerous cells, called blast cells, make up less than 5% of bone marrow cells. The phase usually lasts several years and is well controlled by drug treatment. A blast crisis phase follows when the blast cells make up 20 to 30% of the blood or bone marrow. At this stage, the patient’s condition deteriorates as symptoms like anemia and frequent infections worsen.
The UCSD team, led by Catriona Jamieson, director of Stem Cell Research at Moores Cancer Center, compared samples from CML patients. They found that reduced MBNL3, an RNA-binding protein, correlated with progression from the chronic to blast phase. If you took intro biology in high school or college, you may recall that RNA acts as a messenger molecule critical to translating DNA’s genetic code into proteins. Some splicing and trimming of the RNA molecule prepare it for translation. The decrease in MBNL3 in blast phase cells frees up stretches of RNA, leading to alternative splicing and, in turn, alternative forms of a given protein.
The study showed that, in response to decreased MBNL3, an alternate form of the protein CD44, aptly named CD44 variant 3 (CD44v3), increases in CML blast-phase cells compared with chronic-phase cells. Artificially overproducing CD44v3 increased SOX2 and OCT4 activity, two genes critical for maintaining embryonic stem cell properties. Genes involved with homing blood cells to the bone marrow were also upregulated.
Promising finding
Together, these data suggest that this not only helps CML blast-phase cells preserve stem cell-like qualities, but also helps sequester them in the bone marrow. Other studies have shown that BCR-ABL inhibitor drugs are not effective at eradicating blast-phase cells in the bone marrow. This may explain relapses in some CML patients.
To eliminate these hidden blast-phase cells, the team tested a combination of a CD44 inhibitor and a BCR-ABL inhibitor. Only the combination significantly reduced bone marrow cell survival.
This result motivated the Jamieson team to pursue clinical development of a CD44-blocking antibody in combination with existing BCR-ABL inhibitors. The CD44-blocking antibody was unstable, so the team needs to develop a new antibody.
But the goal remains the same, as Jamieson mentions in a UCSD press release:
“If we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase [for example, BCR-ABL] inhibitors, we may be able to circumvent cancer relapse – a leading cause of cancer-related mortality.”