Summary We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia. Human leukemic bone marrow was transplanted intrafemorally into NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20 and CD34 were isolated from patient samples and engrafted mice before serial transplantation into primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all the different maturational stages were able to reconstitute and re-establish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage-appropriate genes. These observations have informed a model for leukemia-propagating stem cells in childhood ALL.

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A novel transposon-tagging strategy designed to recover dominant gain-of-function alleles was performed with Arabidopsis by using a Dissociation element with a cauliflower mosaic virus 35s promoter transcribing outward over one terminus.Lines containing transposed copies of this transposon were screened for mutants, and a semidominant mutation affecting plant height, hypocotyl elongation, and fertility was recovered. The pleiotropic effects of this mutation appear to result from a general reduction in cell expansion, and some of the effects are similar to those caused by supplying exogenous ethylene or cytokinin to wild-type seedlings. In addition, the arrangement of cells in some organs, such as the etiolated hypocotyl, is disoqanized. The mutation was called tiny, and the affected gene was cloned by first using transposon sequences to isolate the mutant allele. The predicted protein product of the TlNY gene shows strong homology with the DNA binding domain of a recently identified class of plant transcription factors. This domain, called the APETALAS domain, was initially identified as a duplicated region within the APETALAP gene of Arabidopsis and then as a conserved region between APETALAS and the ethylene responsive element binding proteins of tobacco. In the mutant allele, the Dissociation element is inserted in the untranslated leader of the TlNY gene, 35 bp from the ATG, and the mutant contains a novel transcript that initiates from the cauliflower mosaic virus 35s promoter within the transposon. This transcript is present in greater abundance than the wild-type TlNY transcript; therefore, the semidominant tiny mutation most likely results from increased, or ectopic, expression of the gene.

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Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-‘high-risk’ sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34high and CD34low blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

Only some strains of Rhizobium leguminosarum biovar viciae can efficiently nodulate varieties of peas such as cv. Afghanistan, which carry a recessive allele that blocks efficient nodulation by most western isolates of R.I. viciae. One strain (TOM) which can nodulate cv. Afghanistan peas has a gene (nodX) that is required to overcome the nodulation resistance. Strain TOM makes significantly lower amounts of lipo-oligosaccharide nodulation factors than other strains of R.I. viciae and this effect appears to be due to lower levels of nod gene induction. These nodulation factors are similar to those from other R.I. viciae strains in that they consist of an oligomer of four or five beta 1-4-linked N-acetylglucosamine residues in which the terminal non-reducing glucosamine carries an O-acetyl group and a C18:4 or C18:1 N-acyl group. However, one of the nodulation factors made by strain TOM differs from the factors made by other strains of R.I. viciae in that it carries an O-acetyl group on the C-6 of the reducing N-acetylglucosamine residue. This acetylation is NodX-dependent and the pentameric nodulation factor is acetylated on the reducing N-acetylglucosamine residue whereas the tetrameric nodulation factor is not. Although the nodL gene product is also an O-acetyl transferase (it O-acetylates the C-6 of the terminal non-reducing glucosamine), there is very little similarity between the amino acid sequences of these two acetyl transferases.

NGN (neurogenin), a proneural bHLH (basic helix-loop-helix) transcription factor, plays a central role in promoting neuronal specification and differentiation in many regions of the central nervous system. NGN activity has been shown extensively to be controlled at the transcriptional level. However, in addition, recent findings have indicated that the levels of NGN protein may also be regulated. In the present study, we have demonstrated that NGN protein stability was regulated in both Xenopus embryos and P19 embryonal carcinoma cells, a mammalian neuronal model system. In both systems, NGN was a highly unstable protein that was polyubiquitinated for destruction by the proteasome. NGN binds to DNA in complex with its heterodimeric E-protein partners E12 or E47. We observed that NGN was stabilized by the presence of E12/E47. Moreover, NGN was phosphorylated, and mutation of a single threonine residue substantially reduced E12-mediated stabilization of NGN. Thus E-protein partner binding and phosphorylation events act together to stabilize NGN, promoting its accumulation when it can be active.

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