SummaryBone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination.

The misregulation of transcription plays a key role in the development and maintenance of many human diseases. Direct regulators of transcriptional events are therefore often considered as interesting drug targets. Despite this, many such transcription factors are labelled as 'undruggable' 1 for a range of reasons grounded in the logistics of small molecule drug discovery. These factors range from intrinsic disorder at the protein level, to lack of suitable binding pockets for small molecule ligands. While such an undruggable designation is driving further innovation in medicinal chemistry, 2 it is clearly false to label all transcription factors as such. Nuclear receptors are transcription factors that are responsible for sensing molecules (such as hormones) and, in response, directly regulating the expression of specific subsets of genes. 3 By virtue of their control by small molecules, they are inherently druggable and have long been recognised as drug targets for new medicines. 1,4 There are a large number of approved drugs across many disease indications that target nuclear receptors; from ligands of the estrogen receptor (for example, Tamoxifen) for the treatment of breast cancer, to ligands of the glucocorticoid receptor (for example, Dexamethasone) for anti-inflammatory usage. Nonetheless, there are many more opportunities for the therapeutic exploitation of the nuclear receptor superfamily.REV-ERB is a member of the nuclear receptor family consisting of two similar proteins: REV-ERBα 5 and REV-ERBβ. 6 The name REV-ERB is derived from "reverse-ERB", since the NR1D1 gene that codes for REV-ERBα was mapped on the antisense DNA strand of the ERBA proto-oncogene (THRA, thyroid hormone receptor-α). 5 The closely related NR1D2 gene encodes for the other

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Recent efforts have attempted to convert non-blood cells into hematopoietic stem cells (HSCs) with the goal of generating blood lineages de novo. Here we show that hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can convert a developmentally distant lineage (fibroblasts) into ‘induced hematopoietic progenitors' (iHPs). Functionally, iHPs generate acetylcholinesterase+ megakaryocytes and phagocytic myeloid cells in vitro and can also engraft immunodeficient mice, generating myeloerythoid and B-lymphoid cells for up to 4 months in vivo. Molecularly, iHPs transcriptionally resemble native Kit+ hematopoietic progenitors. Mechanistically, reprogramming factor Lmo2 implements a hematopoietic programme in fibroblasts by rapidly binding to and upregulating the Hhex and Gfi1 genes within days. Moreover the reprogramming transcription factors also require extracellular BMP and MEK signalling to cooperatively effectuate reprogramming. Thus, the transcription factors that orchestrate embryonic hematopoiesis can artificially reconstitute this programme in developmentally distant fibroblasts, converting them into engraftable blood progenitors.