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Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n  = 28, tAML: n  = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53 , and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms. Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.

Key messageUsing a time-course RNA-seq analysis we identified transcriptomic changes during formation of nodule-like structures (NLS) in rice and compared rice RNA-seq dataset with a nodule transcriptome dataset in Medicago truncatula.Plant hormones can induce the formation of nodule-like structures (NLS) in plant roots even in the absence of bacteria. These structures can be induced in roots of both legumes and non-legumes. Moreover, nitrogen-fixing bacteria can recognize and colonize these root structures. Therefore, identifying the genetic switches controlling the NLS organogenesis program in crops, especially cereals, can have important agricultural implications. Our recent study evaluated the transcriptomic response occurring in rice roots during NLS formation, 7 days post-treatment (dpt) with auxin, 2,4-D. In this current study, we investigated the regulation of gene expression occurring in rice roots at different stages of NLS formation: early (1-dpt) and late (14-dpt). At 1-dpt and 14-dpt, we identified 1662 and 1986 differentially expressed genes (DEGs), respectively. Gene ontology enrichment analysis revealed that the dataset was enriched with genes involved in auxin response and signaling; and in anatomical structure development and morphogenesis. Next, we compared the gene expression profiles across the three time points (1-, 7-, and 14-dpt) and identified genes that were uniquely or commonly differentially expressed at all three time points. We compared our rice RNA-seq dataset with a nodule transcriptome dataset in Medicago truncatula. This analysis revealed there is some amount of overlap between the molecular mechanisms governing nodulation and NLS formation. We also identified that some key nodulation genes were not expressed in rice roots during NLS formation. We validated the expression pattern of several genes via reverse transcriptase polymerase chain reaction (RT-PCR). The DEGs identified in this dataset may serve as a useful resource for future studies to characterize the genetic pathways controlling NLS formation in cereals.

Several studies have shown that plant hormones play important roles during legume-rhizobia symbiosis. For instance, auxins induce the formation of nodule-like structures (NLSs) on legume roots in the absence of rhizobia. Furthermore, these NLS can be colonized by nitrogen-fixing bacteria, which favor nitrogen fixation compared to regular roots and subsequently increase plant yield. Interestingly, auxin also induces similar NLS in cereal roots. While several genetic studies have identified plant genes controlling NLS formation in legumes, no studies have investigated the genes involved in NLS formation in cereals. In this study, first we established an efficient experimental system to induce NLS in rice roots, using auxin, , consistently at a high frequency (>90%). We were able to induce NLS at a high frequency in under similar conditions. NLS were characterized by a broad base, a diffuse meristem, and increased cell differentiation in the vasculature. Interestingly, NLS formation appeared very similar in both rice and , suggesting a similar developmental program. We show that NLS formation in both rice and occurs downstream of the common symbiotic pathway. Furthermore, NLS formation occurs downstream of cytokinin-induced step(s). We performed a comprehensive RNA sequencing experiment to identify genes differentially expressed during NLS formation in rice and identified several promising genes for control of NLS based on their biological and molecular functions. We validated the expression patterns of several genes using reverse transcription polymerase chain reaction and show varied expression patterns of these genes during different stages of NLS formation. Finally, we show that NLS induced on rice roots under these conditions can be colonized by nitrogen-fixing bacteria, .

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors. Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.

Nitrogen availability is a limiting factor for cereal crop production leading to an excessive use of fertilizers. Taking advantage of plant-microbe symbioses like legume-rhizobia symbiosis is one option for exploring a natural nitrogen source for cereal plants, such as rice. Legumes can develop a symbiotic association with soil bacteria, rhizobia, that leads to the formation of specialized root structures, nodules, inside which nitrogen fixation can occur. Unfortunately, this symbiosis is species-specific and is restricted only to legumes. Therefore, cereals are still heavily dependent on fertilizers for their nitrogen needs. Several studies have shown that plant hormones, like auxin, play important roles during legume-rhizobia symbiosis. For instance, application of auxin transport inhibitors to legume roots induces the formation of nodule-like structures (NLS) in the absence of rhizobia. Furthermore, these NLS can be colonized by rhizobia and successful nitrogen fixation can occur inside them. Interestingly, auxin also induces similar NLS in cereal roots. While several genetic studies have identified plant genes controlling NLS formation in legumes, unfortunately, no studies have investigated the genes involved in NLS formation in cereals. In this study, we were successful in inducing NLS in rice and Medicago roots, using auxin, 2,4-D, consistently at a high frequency (>90%) under controlled sterile conditions. These structures were characterized by a broad base, a diffuse meristem, and increased cell differentiation in the vasculature. Interestingly, they were found to be structurally similar in rice and Medicago, suggesting a similar developmental program across cereals and legumes. Genetic studies in rice and Medicago using available symbiotic mutants indicated that formation of NLS did not depend on the ‘Common Symbiotic Pathway’, which is required for both legume-rhizobia and arbuscular mycorrhizal symbioses. These results further suggested that a similar genetic program might control NLS formation across cereals and legumes. Next, we performed a comprehensive RNA-Sequencing experiment to identify the differentially expressed genes during NLS formation in rice. We identified genes at early and later stages of NLS formation. Interestingly, we identified several orthologs of genes, which have been shown to play a role in legume-rhizobia symbiosis. Finally, we validated the expression pattern of thirteen candidate genes belonging to five gene classes (hormone related, growth and development, transcription factors, receptor kinases, and transport related) using RT-PCR. Future efforts can focus on identifying and validating the expression pattern of additional candidate genes and genetically characterizing them. These studies will make important advances towards improving nitrogen fixation in cereals and will have a positive impact on sustainable agriculture worldwide.

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.Competing Interest StatementS.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Accent Therapeutics, and Nimbus Therapeutics. S.A.A. has received research support from Janssen, Novartis, and Syndax. S.A.A. is an inventor on a patent related to MENIN inhibition WO/2017/132398A1. C.G.M. has received research funding from AbbVie and Pfizer unrelated to this work, compensation for advisory board membership of Illumina, speaking and travel fees from Amgen, and holds stock in Amgen.Footnotes* The author order on the BioRxiv web page was incorrect. It has been updated to reflect the correct order shown in the pdf.