Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases.

BACKGROUND: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder MVK deficiency. So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported. OBJECTIVES: This study reports the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK. METHODS: The investigators performed whole-exome sequencing and functional studies in cells from a patient who, on clinical and immunological evaluation, was suspected of an autoinflammatory disease. RESULTS: The investigators identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities as well as distinct features compared to patients with MVK deficiency and responded well to therapeutic IL-1 inhibition. CONCLUSIONS: This study reported the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK, leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia and thus should be included in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.

Extra centrosomes delay DNA damage-driven tumorigenesis.

Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, Caspase-2, Raidd/Cradd, or Pidd1. BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.

Apoptosis as a Barrier against CIN and Aneuploidy.

Aneuploidy is the gain or loss of entire chromosomes, chromosome arms or fragments. Over 100 years ago, aneuploidy was described to be a feature of cancer and is now known to be present in 68-90% of malignancies. Aneuploidy promotes cancer growth, reduces therapy response and frequently worsens prognosis. Chromosomal instability (CIN) is recognized as the main cause of aneuploidy. CIN itself is a dynamic but stochastic process consisting of different DNA content-altering events. These can include impaired replication fidelity and insufficient clearance of DNA damage as well as chromosomal mis-segregation, micronuclei formation, chromothripsis or cytokinesis failure. All these events can disembogue in segmental, structural and numerical chromosome alterations. While low levels of CIN can foster malignant disease, high levels frequently trigger cell death, which supports the "aneuploidy paradox" that refers to the intrinsically negative impact of a highly aberrant karyotype on cellular fitness. Here, we review how the cellular response to CIN and aneuploidy can drive the clearance of karyotypically unstable cells through the induction of apoptosis. Furthermore, we discuss the different modes of p53 activation triggered in response to mitotic perturbations that can potentially trigger CIN and/or aneuploidy.

Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis.

Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice. Moreover, total ablation of Chk1 in B-cells arrests their development at the pro-B cell stage, a block that, surprisingly, cannot be overcome by inhibition of mitochondrial apoptosis, as cell cycle arrest is initiated as an alternative fate to limit the spread of damaged DNA. Our findings define CHK1 as essential in B-cell development and potent target to treat blood cancer.