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Key Points LMO2 is deacetylated by the NAMPT/SIRT2 pathway. LMO2 deacetylation is essential for LIM domain binding 1 binding and TAL1 complex activation during hematopoiesis and T-ALL leukemogenesis.

Some twenty cases of dispermic chimeras with the karyotype 46,XX/46,XY, discovered because of gonadal dysplasias or a true hermaphroditism, have been reported. This is a report of a phenotypically normal man with 46,XX/46,XY chimerism in whom a prepubertal finding of positive X-chromatin was interpreted as Klinefelter syndrome. The diagnosis was revised 11 years later when the family doctor, who doubted the earlier diagnosis because of the patient's normal-sized testes, sent him to an outpatient clinic. The young man was 23 years old, athletic (74kg, 180cm), with normal body proportions, normal sexual hair distribution, normal libido and potency, normal endocrine parameters, and a normal spermiogram. The karyotype revealed an XX/XY mosaic in a proportion of 1:2. An identical set of maternal markers (Q- and C-banding) was present in male and female cells. Differences were found with respect to two paternal markers. Furthermore, blood, serum, and red cell enzyme groups in five systems showed two phenotypes, again with duality of paternal origin. It is concluded that a positive X-chromatin in prepuperty, especially in the absence of supporting clinical features, must be followed by a karyotype study.

Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. We change a protein fold by rearranging the sequence and optimising it towards the new fold. Testing four designs, we obtain two that possess nanomolar activity, the most active of which is highly thermostable and protease-resistant, and matches its designed structure to atomic accuracy. While the designs possess starkly different sequence and structure from the native G-CSF, they show specific activity in differentiating primary human haematopoietic stem cells into mature neutrophils. The designs also show significant and specific activity in vivo. Our topological refactoring approach is largely independent of sequence or structural context, and is therefore applicable to a wide range of protein targets.

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