Overexpression of stem cell associated ALDH1A1, a target of the leukemogenic transcription factor TLX1/HOX11, inhibits lymphopoiesis and promotes myelopoiesis in murine hematopoietic progenitors

TLX1/HOX11 is an oncogenic transcription factor in human T-cell leukemia, however, the molecular basis for its transforming activity has remained elusive. The ALDH1A1 gene, whose product participates in retinoic acid synthesis, was previously identified as a TLX1-responsive gene. Here, we confirm regulation of ALDH1A1 transcription by TLX1 and show that ALDH1A1 can profoundly perturb murine hematopoiesis by promoting myeloid differentiation at the expense of lymphopoiesis. Together, these data demonstrate that ALDH1A1 plays a key role in normal hematopoiesis, and confirm ALDH1A1 as a TLX1 transcriptional target that may contribute to the ability of this homeoprotein to alter cell fate and induce tumor growth

TLX1/HOX11 transcription factor inhibits differentiation and promotes a non-haemopoietic phenotype in murine bone marrow cells

The TLX/HOX11 subfamily of divergent homeobox genes are involved in various aspects of embryogenesis and, in the case of TLX1/HOX11 and TLX3/HOX11L2, feature prominently as oncogenes in human T-cell acute lymphoblastic leukaemia. TLX1 possesses immortalising activity in a wide variety of blood cell lineages, however, the effect of this oncogene on haemopoietic cell differentiation has not been fully investigated. We therefore constitutively expressed TLX1 in murine bone marrow or fetal liver cells using retroviral transfer followed by transplantation and/or in vitro culture. TLX1 was found to dramatically alter haemopoiesis, promoting the emergence of a non-haemopoietic CD45- CD31+ cell population while markedly inhibiting erythroid and granulocytic cell differentiation. To identify genetic programs perturbed by TLX1, a comparison of transcript profiles from J2E erythroid cells with and without enforced TLX1 expression was undertaken. This revealed a pattern of gene expression indicative of enhanced proliferation coupled to differentiation arrest. Of the genes identified, two, KIT and VEGFC, were found to be potential TLX1 targets based on transcriptional assays. These results demonstrate that TLX1 can act broadly to impair haemopoiesis and divert differentiation to an alternative fate. This may account for its ability to promote the pre-leukaemic state via perturbation of specific gene expression programs

Ancient and recycled sulfur sampled by the Iceland mantle plume

Stable sulfur isotope ratios of mid-ocean ridge and ocean island basalts (MORBs and OIBs) preserve unique information about early Earth processes and the long-term volatile cycles between Earth's mantle and the surface. Icelandic basalts present ideal material to examine the oldest known terrestrial mantle reservoir, accessed through a deep-rooted mantle plume, but their multiple sulfur isotope systematics have not been explored previously. Here, we present new sulfur concentration (30–1570 ppm) and isotope data (ẟ34S = −2.5 to +3.8‰ and Δ33S = −0.045 to +0.016‰; vs. Canyon Diablo Troilite) from a sample suite (n = 62) focused on subglacially erupted basaltic glasses obtained from Iceland's neovolcanic zones. Using these data along with trace element systematics to account for the effects of magmatic processes (degassing and immiscible sulfide melt formation) on ẟ34S, we show that primitive (MgO > 6 wt.%), least degassed glasses accurately record the ẟ34S signatures of their mantle sources. Compared to the depleted MORB source mantle (DMM; ẟ34S = −1.3±0.3‰), the Iceland mantle is shown to have a greater range of ẟ34S values between −2.5 and −0.1%. Similarly, Icelandic basalts are characterized by more variable and negatively shifted Δ33S values (−0.035 to +0.013‰) relative to DMM (0.004±006‰). Negative low-ẟ34S-Δ33S signatures are most prominent in basalts from the Snæfellsnes Volcanic Zone and the Kverkfjöll volcanic system, which also have the lowest, most MORB-like 3He/4He (8–9 R/RA, where RA is the 3He/4He of air) and the highest Ba/La (up to 12) in Iceland. We propose that subduction fluid-enriched, mantle wedge type material, possibly present in the North Atlantic upper mantle, constitutes a low-ẟ34S-Δ33S component in the Icelandic mantle. This suggests that volatile heterogeneity in Iceland, and potentially at other OIBs, may originate not only from diverse plume-associated mantle components, but also from a heterogeneous ambient upper mantle. By contrast, a set of samples with high 3He/4He (up to 25.9 R/RA) and negative μ182W anomalies define an ancient lower mantle reservoir with a near-chondritic Δ33S and ẟ34S signature of ∼0‰. The difference between DMM and the high high-3He/4He mantle may reflect separate conditions during core-mantle differentiation, or a previously unidentified flux of sulfur from the core to the high-3He/4He reservoir