ALL, a cancer of the bone marrow affecting 4,000 US residents annually, is characterized by the over-production of immature white blood cells. An aggressive form of ALL results from a chromosomal translocation, known as the Philadelphia chromosome (Ph), in which segments from chromosomes 9 and 22 are aberrantly fused together. Ph+ ALL is far more prevalent in adults (~30% of adult ALL) than in children (~4% of pediatric ALL), but it carries a poor prognosis in both age groups. Ph+ cells express a protein (encoded by an oncogene created by the chromosome fusion) called BCR-ABL. BCR-ABL is a constitutively active enzyme, a tyrosine kinase, which promotes uncontrolled cell proliferation.
Continuous treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, has revolutionized the therapy of another form of Ph+ cancer, chronic myelogenous leukemia (CML), by inducing durable remissions. However, the response of Ph+ ALL patients is not nearly as good, leading to shorter remissions and more rapid emergence of imatinib resistance. In general, Ph+ CML and ALL patients that fail imatinib therapy develop mutations in the BCR-ABL kinase that make them drug-resistant, but the reasons underlying the increased rate of emergence of mutant clones in Ph+ ALL has not been satisfactorily explained.
Williams and colleagues tracked the development of imatinib resistance, using a mouse model of Ph+ ALL. They engineered BCR-ABL-expressing lymphocyte progenitors that also lack the tumor suppressor protein ARF (which is deleted in more than 30% of Ph+ ALL patients, but not in CML patients, at their time of diagnosis). Interestingly, ARF-deficient lymphocytes expressing BCR-ABL were so highly aggressive that inoculation of as few as 20 such cells into healthy mice induced fatal ALL in less than 3 weeks. “Although experiments with CML support the concept that these leukemias arise from a rare population of ‘cancer stem cells’, our work on Ph+ ALL emphasizes that this need not be the case,” says Williams.
Further genetic experiments revealed that signals from the bone marrow micro-environment of the host animals were able to sustain the viability of ARF-deficient leukemia cells in the face of imatinib therapy. “We suspect that similar signals may nurture ARF-deficient Ph+ ALL cells in patients,” says Sherr, “thereby allowing the rapid emergence of imatinib-resistant clones.”
Heather Cosel | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences