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News From The Journal Of Clinical Investigation: July 16, 2012

ONCOLOGY A new target in

Acute myeloid leukemia, a common leukemia in adults, is characterized by aberrant proliferation of cancerous bone marrow cells. Activating mutations in a protein receptor known as FLT3 receptor are among the most prevalent mutations observed in acute myeloid leukemias. FLT3 mutants are thought to activate several signaling pathways that contribute to . Dr. Daniel Tenen and from in Boston discovered a new pathway activated by FLT3 mutation. Their results show that 1 (CDK1), a critical regulator of cell division is activated in FLT3 mutated leukemias, leading to the activation of downstream gene transcription. Most importantly, they demonstrate that inhibiting CDK1 activity promotes differentiation of cells from patient-derived peripheral blood samples. As clinical trials with CDK1 inhibitors are ongoing, their data strongly suggest that therapies targeting the CDK1 pathway may be efficacious for acute myeloid leukemias with FLT3 mutation, especially in patients resistant to FLT3 inhibitor therapies.

TITLE: Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα


ONCOLOGY A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers raises the possibility that changes in few genes that regulate chromatin structure and gene expression are capable of driving cancer formation. Dr. Charles Roberts and colleauges at the Dana-Farber Cancer Institute in Boston sequenced the expressed genes of rhabdoid tumors, highly aggressive cancers of early childhood. These tumors typically exhibit loss of a protein known as SMARCB1, a subunit of the that is important in controlling gene transcription. The Roberts group identified an extremely low rate of mutations, with loss of SMARCB1 as the only recurrent event. Their results demonstrate that high mutation rates are typically associated with cancer development is not required in all tumors, particularly for cancers driven by mutation of a . Thus, remarkably simple genetic changes can underlie cancer development.

TITLE: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers


ONCOLOGY PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response

The DNA damage response (DDR) is a complex regulatory network that is critical for maintaining genome integrity. Posttranslational modifications are widely used to ensure strict spatiotemporal control of signal flow, but how the DDR responds to environmental cues, such as changes in ambient oxygen tension, remains poorly understood. Cam Patterson and colleagues at the University of North Carolina found that an essential component of the ATR/CHK1 signaling pathway, known as HCLK2, associated with and was hydroxylated by prolyl hydroxylase domain protein 3 (PHD3). HCLK2 hydroxylation was necessary for its interaction with ATR and the subsequent activation of the DDR. Inhibiting PHD3 prevented activation of the ATR/CHK1/p53 pathway and decreased cell death induced by DNA damage. Consistent with these observations, they found that mice lacking PHD3 were resistant to the effects of ionizing radiation and had decreased thymic apoptosis, a biomarker of genomic integrity.

TITLE: PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response


OPHTHALMOLOGY Inflammation and age-related retinal degeneration

Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Post-mitotic neurons, such as photoreceptor cells in the retina, and the adjacent retinal pigmented epithelium that together maintain vision, are especially susceptible to age-related retinal degeneration (ARD). The multi-genic etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the background genetic differences that drive the phenotypic progression of ARD, Dr. Krzysztof Palczewski and colleagues at Case Western University in Cleveland, OH studied a strain of mice that develop more pronounced ARD than other inbred mouse models. Using state-of-the-art genetic analysis, they identified several genetic changes that cause an increased predisposition to ARD in mice. These insights may further improve our understanding of susceptible genetic loci that drive disease involved in age-associated disorders, including several human blinding diseases.

TITLE: Inflammatory priming predisposes to age-related retinal degeneration in mice



Journal of Clinical Investigation