bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–10–27
fiveteen papers selected by
William Grey, University of York
  1. Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors.
  2. Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression.
  3. Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients.
  4. Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice.
  5. Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.
  6. Interleukin-1β modulates lymphoid differentiation of Flt3-positive multipotent progenitors after transplantation.
  7. Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis.
  8. IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow.
  9. The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies.
  10. MALAT1/miR-582-5p/GALNT1/MUC1 axis modulates progression of AML leukemia stem cells by regulating JAK2/STAT3 pathway.
  11. NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.
  12. Integrative phosphoproteomic analysis reveal hemostatic-endothelial signaling interplay.
  13. MSI2 mediates WNT/β-Catenin pathway function in hematopoietic stem cells.
  14. Development of a quantitative prediction algorithm for human cord blood-derived CD34+ hematopoietic stem-progenitor cells using parametric and non-parametric machine learning models.
  15. Cellular Mechanisms of RET Receptor Dysfunction in Multiple Endocrine Neoplasia 2.
  1. Blood. 2024 Oct 22. pii: blood.2024024769. [Epub ahead of print]
    Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors.
    Stefano Comazzetto, Daniel Cassidy, Andrew W DeVilbiss, Elise Jeffery, Bethany Ottesen, Amanda Reyes, Animesh Paul, Suraj Bansal, Stephanie Z Xie, Sarah Muh, Thomas Mathews, Brandon Chen, Zhiyu Zhao, Sean J Morrison.
      Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development, partly by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter from hematopoietic cells depleted ascorbate to undetectable levels in HSCs and MPPs without altering plasma ascorbate levels. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potentials of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate deficiency confers MPPs with long-term self-renewal potential.
    DOI:  https://doi.org/10.1182/blood.2024024769
  2. Cell Tissue Res. 2024 Oct 22.
    Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression.
    Emanuela Chiarella.
      Hematopoietic stem cells (HSCs) drive cellular turnover in the hematopoietic system by balancing self-renewal and differentiation. In the adult bone marrow (BM), these cells are regulated by a complex cellular microenvironment known as "niche," which involves dynamic interactions between diverse cellular and non-cellular elements. During blood cell maturation, lineage branching is guided by clusters of genes that interact or counteract each other, forming complex networks of lineage-specific transcription factors. Disruptions in these networks can lead to obstacles in differentiation, lineage reprogramming, and ultimately malignant transformation, including acute myeloid leukemia (AML). Zinc Finger Protein 521 (Znf521/Zfp521), a conserved transcription factor enriched in HSCs in both human and murine hematopoiesis, plays a pivotal role in regulating HSC self-renewal and differentiation. Its enforced expression preserves progenitor cell activity, while inhibition promotes differentiation toward the lymphoid and myeloid lineages. Transcriptomic analysis of human AML patient samples has revealed upregulation of ZNF521 in AMLs with the t(9;11) fusion gene MLL-AF9. In vitro studies have shown that ZNF521 collaborates with MLL-AF9 to enhance the growth of transformed leukemic cells, increase colony formation, and activate MLL target genes. Conversely, inhibition of ZNF521 using short-hairpin RNA (shRNA) results in decreased leukemia proliferation, reduced colony formation, and induction of cell cycle arrest in MLL-rearranged AML cell lines. In vivo experiments have demonstrated that mZFP521-deficient mice transduced with MLL-AF9 experience a delay in leukemia development. This review provides an overview of the regulatory network involving ZNF521, which plays a crucial role in controlling both HSC self-renewal and differentiation pathways. Furthermore, we examine the impact of ZNF521 on the leukemic phenotype and consider it a potential marker for MLL-AF9+ AML.
    Keywords:  Acute myeloid leukemia (AML); Hematopoietic stem cells (HSCs); MLL-AF9 fusion gene; Myeloid and lymphoid differentiation; Transcription factors; Znf521/Zfp521; t (9;11)
    DOI:  https://doi.org/10.1007/s00441-024-03926-2
  3. Sci Rep. 2024 10 23. 14(1): 25060
    Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients.
    Chenxu Zhu, Thomas Stiehl.
      Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The "7+3 regimen", which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. Since peripheral blood cells are easily accessible to longitudinal sampling, significant research efforts have been undertaken to characterize and reduce adverse effects on circulating blood cells. However, much less is known about the impact of the 7+3 regimen on human hematopoietic stem cells and their physiological micro-environments, the so-called stem cell niches. One reason for this is the technical inability to observe human stem cells in vivo and the discomfort related to bone marrow biopsies. To better understand the treatment effects on human stem cells, we consider a mechanistic mathematical model of the stem cell niche before, during and after chemotherapy. The model accounts for different maturation stages of leukemic and hematopoietic cells and considers key processes such as cell proliferation, self-renewal, differentiation and therapy-induced cell death. In the model, hematopoietic (HSCs) and leukemic stem cells (LSCs) compete for a joint niche and respond to both systemic and niche-derived signals. We relate the model to clinical trial data from literature which longitudinally quantifies the counts of hematopoietic stem like (CD34+CD38-ALDH+) cells at diagnosis and after therapy. The proposed model can capture the clinically observed interindividual heterogeneity and reproduce the non-monotonous dynamics of the hematopoietic stem like cells observed in relapsing patients. Our model allows to simulate different scenarios proposed in literature such as therapy-related impairment of the stem cell niche or niche-mediated resistance. Model simulations suggest that during the post-therapy phase a more than 10-fold increase of hematopoietic stem-like cell proliferation rates is required to recapitulate the measured cell dynamics in patients achieving complete remission. We fit the model to data of 7 individual patients and simulate variations of the treatment protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.
    Keywords:  7+3 chemotherapy; Acute myeloid leukemia (AML); Cancer stem cell; Computational model; Mathematical model; Stem cell niche
    DOI:  https://doi.org/10.1038/s41598-024-75429-7
  4. Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00358-8. [Epub ahead of print]
    Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice.
    Rong Mou, Junkai Ma, Xuan Ju, Yixin Wu, Qiuli Chen, Jinglin Li, Tongyao Shang, Siying Chen, Yue Yang, Yue Li, Kaosheng Lv, Xuequn Chen, Qi Zhang, Tingbo Liang, Ye Feng, Xinjiang Lu.
      Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.
    Keywords:  arginine vasopressin; bone marrow; depression; hematopoietic stem cells; neuroinflammation
    DOI:  https://doi.org/10.1016/j.stem.2024.09.018
  5. Science. 2024 Oct 24. eado6836
    Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.
    Julia Phan, Brandon Chen, Zhiyu Zhao, Gabriele Allies, Antonella Iannaccone, Animesh Paul, Feyza Cansiz, Alberto Spina, Anna-Sophia Leven, Alexandra Gellhaus, Dirk Schadendorf, Rainer Kimmig, Marcel Mettlen, Alpaslan Tasdogan, Sean J Morrison.
      Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and LINE elements. Retrotransposon transcription activates the innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in non-pregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN regulated genes were also induced in mouse HSCs after serial bleeding and in human HSCs during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant, but not non-pregnant, people suggesting conservation of these mechanisms from mice to humans.
    DOI:  https://doi.org/10.1126/science.ado6836
  6. Cell Rep. 2024 Oct 18. pii: S2211-1247(24)01241-5. [Epub ahead of print]43(11): 114890
    Interleukin-1β modulates lymphoid differentiation of Flt3-positive multipotent progenitors after transplantation.
    Jing Xia, Lisi Lan, Chenyu You, Li Tang, Tao Chen, Yunqiao Yang, Li Lin, Jianlong Sun.
      Myeloablative pre-conditioning facilitates the differentiation of transplanted hematopoietic stem and progenitor cells (HSPCs). However, the factors in the stress environment that regulate HSPC behavior remain elusive. Here, we investigated the mechanisms that shaped the cell fates of transplanted murine multipotent progenitors (MPPs) expressing the Fms-related receptor tyrosine kinase 3 gene (Flt3). Using lineage tracing, clonal analysis, and single-cell RNA sequencing (RNA-seq), we showed that the myeloablative environment increased lymphoid priming of Flt3+ MPPs and that their efficient B cell output required intact interleukin 1 (IL-1) signaling. The Flt3+ MPPs with short-term exposure to IL-1β underwent a myeloid-biased to lymphoid-biased cell fate switch and produced more lymphoid-biased progeny with a stronger B lymphopoiesis capacity in vitro. Correspondingly, a brief exposure to IL-1β facilitated the B cell output of transplanted Flt3+ MPPs in vivo. Together, our study demonstrated an unrecognized function of IL-1β in promoting B lymphopoiesis and highlighted a latent effect of IL-1β in regulating MPP cell fate dynamics.
    Keywords:  CP: Stem cell research; IL-1; cell fate switch; differentiation; multipotent progenitor; transplantation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114890
  7. Nat Commun. 2024 Oct 24. 15(1): 9189
    Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis.
    Ashley E Culver-Cochran, Aishlin Hassan, Kathleen Hueneman, Kwangmin Choi, Averil Ma, Brett VanCauwenbergh, Eric O'Brien, Mark Wunderlich, John P Perentesis, Daniel T Starczynowski.
      Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant. Herein, we show that AML patients who experience induction failure have elevated expression of the NF-κB target gene tumor necrosis factor alpha-induced protein-3 (TNFAIP3/A20) and impaired necroptotic cell death. A20High AML are resistant to anthracyclines, while A20Low AML are sensitive. Loss of A20 in AML restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML.
    DOI:  https://doi.org/10.1038/s41467-024-53629-z
  8. Blood. 2024 10 22. pii: blood.2024024258. [Epub ahead of print]
    IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow.
    Qi Lou, Kaizheng Jiang, Xiaoqi Wang, Yuan Pan, Guo Qiu, Binghuo Wu, Lisha Yuan, Siyu Xie, Jian Chen, Quanhui Xu, Meng Zhao, Linjia Jiang.
      During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, while bone marrow becomes the primary site for definitive hematopoiesis, the establishment of the bone marrow niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal bone marrow mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared to adult BMSCs. Deletion of Igf1r in perinatal BMSCs hinders the transition of HSCs from the fetal liver to the bone marrow in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in adult BMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the bone marrow. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 (NFATc1) in perinatal BMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in perinatal BMSCs regulates the development of the bone marrow niche for hematopoiesis.
    DOI:  https://doi.org/10.1182/blood.2024024258
  9. Leukemia. 2024 Oct 22.
    The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies.
    Mengge Yu, Giselle Sek Suan Nah, Vaidehi Krishnan, Fatin Nasha Bte Sulaimi, King Pan Ng, Chuqi Wang, Shruti Bhatt, Charles Chuah, David E Bergstrom, S Tiong Ong.
      One sixth of human cancers harbor pathogenic germline variants, but few studies have established their functional contribution to cancer outcomes. Here, we developed a humanized mouse model harboring a common East Asian polymorphism, the BIM deletion polymorphism (BDP), which confers resistance to oncogenic kinase inhibitors through generation of non-apoptotic splice isoforms. However, despite its clear role in mediating bulk resistance in patients, the BDP's role in cancer stem and progenitor cells, which initiate disease and possess altered BCL-2 rheostats compared to differentiated tumor cells, remains unknown. To study the role of the BDP in leukemia initiation, we crossed the BDP mouse into a chronic myeloid leukemia (CML) model. We found that the BDP greatly enhanced the fitness of CML cells with a three-fold greater competitive advantage, leading to more aggressive disease. The BDP conferred almost complete resistance to cell death induced by imatinib in CML stem and progenitor cells (LSPCs). Using BH3 profiling, we identified a novel therapeutic vulnerability of BDP LSPCs to MCL-1 antagonists, which we confirmed in primary human LSPCs, and in vivo. Our findings demonstrate the impact of human polymorphisms on the survival of LSPCs and highlight their potential as companion diagnostics for tailored therapies.
    DOI:  https://doi.org/10.1038/s41375-024-02418-0
  10. Ann Hematol. 2024 Oct 21.
    MALAT1/miR-582-5p/GALNT1/MUC1 axis modulates progression of AML leukemia stem cells by regulating JAK2/STAT3 pathway.
    Si Li, Rui Gao, Xu Han, Kai Wang, Bingyu Kang, Xiaolu Ma.
      Acute myeloid leukemia (AML) is characterized by uncontrolled clonal expansion and differentiation block of immature myeloid cells. Some studies have shown that leukemia stem cells (LSC) are thought to be responsible for the initiation and development of leukemia. Moreover, abnormal O-glycosylation is a key modification in the process of cancer malignancy. In this study, GALNT1 expression was significantly upregulated in LSCs, while knockdown of GALNT1 inhibited cell viability and promoted apoptosis. Importantly, GALNT1 was the direct target of miR-582-5P, and MALAT1 directly interacted with miR-582-5P. In addition, Our investigation corroborated that MALAT1 functioned as an endogenous sponge of miR-582-5P to regulate mucin1 (MUC1) expression, catalyzed by GALNT1, which modulated the activity of JAK2/STAT3 pathway. MALAT1 and MUC1 were targets of transcription factor STAT3 and were regulated by STAT3. In general, these new findings indicated that MALAT1/miR-582-5P/GALNT1 axis is involved in the progression of LSCs, illuminating the possible mechanism mediated by O-glycosylated MUC1 via JAK2/STAT3 pathway.
    Keywords:  AML; GALNT1; LSCs; MALAT1; MUC1; miR-582-5p
    DOI:  https://doi.org/10.1007/s00277-024-06043-w
  11. Leukemia. 2024 Oct 23.
    NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.
    Yuko Shimosato, Keita Yamamoto, Yuhan Jia, Wenyu Zhang, Norio Shiba, Yasuhide Hayashi, Shuichi Ito, Toshio Kitamura, Susumu Goyama.
      Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.
    DOI:  https://doi.org/10.1038/s41375-024-02438-w
  12. J Thromb Haemost. 2024 Oct 21. pii: S1538-7836(24)00618-4. [Epub ahead of print]
    Integrative phosphoproteomic analysis reveal hemostatic-endothelial signaling interplay.
    Stijn A Groten, Bart L van den Eshof, Floris P J van Alphen, Alexander B Meijer, Maartje van den Biggelaar, Arie J Hoogendijk.
       BACKGROUND: The vascular endothelial cell (EC) monolayer plays a crucial part in maintaining hemostasis. An extensive array of G protein-coupled receptors (GPCRs) allows ECs to dynamically act on key hemostatic stimuli such as thrombin and histamine. The impact of these individual stimuli on EC signal transduction has been the subject of various studies, but insight into discordant and concordant EC signaling between different GPCRs remain limited.
    OBJECTIVES: To elucidate histamine and protease activated receptor (PAR1-4) signaling cascades in endothelial cells, discern overlapping and diverging regulation between these stimuli and their effect on the EC monolayer.
    METHODS: We employed stable isotope labelling by amino acids in cell culture (SILAC) mass spectrometry-based phosphoproteomics on in vitro cultured BOECs, stimulated with histamine and different protease activated receptor peptides (PAR1-4). We investigated key phosphosites through immuno(fluorescence)- staining and determined effects on barrier function through trans endothelial resistance assays.
    RESULTS: EC histamine activation initiated an extensive (kinase-) signaling network (among which, MAPK3, STAT3 and CTNND1). PAR1 and PAR2 receptors induced highly similar signaling cascades, wheras PAR3 and PAR4 induced minimal phospho-regulation. Integration of all applied stimuli indicated uniquely activated proteins between both stimuli, as well as a general overlapping activation of cell-junction and actin cytoskeletal proteins.
    CONCLUSION: We provide an integrative phosphoproteomic analysis of histamine and PAR agonists in the endothelium that highlights the endothelial response programs that are at the bases of regulating hemostasis.
    Keywords:  Endothelial cells; Protease Activated Receptors; SILAC; histamine; mass spectrometry; phosphoproteomics; signal transduction
    DOI:  https://doi.org/10.1016/j.jtha.2024.10.011
  13. Leukemia. 2024 Oct 22.
    MSI2 mediates WNT/β-Catenin pathway function in hematopoietic stem cells.
    Huifang Zhang, Ruixue Guo, Zhenfen Li, Rui Ma, Shina Xu, Le Yin, Hongkai Zhu, Zineng Huang, Cheng Xing, Yunlong Yang, Yulin Pu, Zhao Cheng, Jing Liu, Hongling Peng, Yue Sheng.
      
    DOI:  https://doi.org/10.1038/s41375-024-02447-9
  14. Sci Rep. 2024 10 23. 14(1): 25085
    Development of a quantitative prediction algorithm for human cord blood-derived CD34+ hematopoietic stem-progenitor cells using parametric and non-parametric machine learning models.
    Chi-Kwan Leung, Pengcheng Zhu, Ian Loke, Kin Fai Tang, Ho-Chuen Leung, Chin-Fung Yeung.
      The transplantation of CD34+ hematopoietic stem-progenitor cells (HSPCs) derived from cord blood serves as the standard treatment for selected hematological, oncological, metabolic, and immunodeficiency disorders, of which the dose is pivotal to the clinical outcome. Based on numerous maternal and neonatal parameters, we evaluated the predictive power of mathematical pipelines to the proportion of CD34+ cells in the final cryopreserved cord blood product adopting both parametric and non-parametric algorithms. Twenty-four predictor variables associated with the cord blood processing of 802 processed cord blood units randomly sampled in 2020-2022 were retrieved and analyzed. Prediction models were developed by adopting the parametric (multivariate linear regression) and non-parametric (random forest and back propagation neural network) statistical models to investigate the data patterns for determining the single outcome (i.e., the proportion of CD34+ cells). The multivariate linear regression model produced the lowest root-mean-square deviation (0.0982). However, the model created by the back propagation neural network produced the highest median absolute deviation (0.0689) and predictive power (56.99%) in comparison to the random forest and multivariate linear regression. The predictive model depending on a combination of continuous and discrete maternal with neonatal parameters associated with cord blood processing can predict the CD34+ dose in the final product for clinical utilization. The back propagation neural network algorithm produces a model with the highest predictive power which can be widely applied to assisting cell banks for optimal cord blood unit selection to ensure the highest chance of transplantation success.
    Keywords:  AABB; CAP; Cord blood bank; FACT; Hematopoietic stem cells; Unrelated hematopoietic stem cell transplant
    DOI:  https://doi.org/10.1038/s41598-024-75731-4
  15. Endocr Relat Cancer. 2024 Oct 01. pii: ERC-24-0187. [Epub ahead of print]
    Cellular Mechanisms of RET Receptor Dysfunction in Multiple Endocrine Neoplasia 2.
    Timothy J Walker, Lois M Mulligan.
      REarranged during Transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point-mutations give rise to the inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of ligand. These mutations cause intrinsic biochemical changes in RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.
    DOI:  https://doi.org/10.1530/ERC-24-0187
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