Mutant KRAS Copy-Number Gain Drives Metabolic Reprogramming [Metabolism]

Homozygous and heterozygous KRAS mutant cancer cells have distinct metabolic phenotypes.

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Noted [News in Brief]

A collection of recently published news items.

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Tracking Tumor Evolution through Mathematics [News in Brief]

A recent study suggests that many cancers undergo neutral evolution, with all key mutations present at the start of malignancy. New mutations acquired along the way don't confer any advantages on tumor cells.

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Mutant CALR Requires Its C-terminus and MPL to Transform [Research Articles]

Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK–STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN.

Significance: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL. Cancer Discov; 6(4); 368–81. ©2016 AACR.

See related commentary by Stanley and Steidl, p. 344.

This article is highlighted in the In This Issue feature, p. 331

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Illumina Spin-off to Develop Early-Detection Test [News in Brief]

DNA-sequencing giant Illumina has formed a new company, called Grail, to develop liquid biopsies capable of spotting cancer before symptoms arise. The start-up is working on a low-cost "pan-cancer" test that can detect multiple cancer types early, which it hopes to introduce by 2019.

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TGF{beta} Mediates Tumor Suppression via Induction of EMT-Linked Apoptosis [Pancreatic Cancer]

TGFβ induces a SMAD4-dependent EMT in the pancreas that promotes apoptosis.

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Expanding the Scope of ENCODE [News in Brief]

The National Human Genome Research Institute has earmarked up to $38 million in grant funding for five new initiatives aimed at expanding ENCODE, its database of functional elements in human and mouse genomes. For the first time, grantees will focus on diseased tissue samples in an effort to understand how these functional elements influence the development of cancer and other diseases.

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