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"Corrigan, David"
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Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential
The role of mitochondria in haematopoietic stem-cell maintenance has not been examined in detail; here mitofusin 2, which modulates mitochondrial fusion and tethering of endoplasmic reticulum to the mitochondria, is shown to be necessary for the maintenance of haematopoietic stem cells with extensive lymphoid potential.
Maintenance of HSC lymphoid potential
The role of mitochondria in maintaining haematopoietic lineages has not been examined in detail. Hans-Willem Snoeck and colleagues have found that the haematopoietic stem cell (HSC) regulator
Prdm16
induces the expression of mitofusin 2 (Mfn2), which modulates mitochondrial fusion and tethering of endoplasmic reticulum to the mitochondria. By adjusting the levels of Mfn2 in HSCs, they demonstrate that Mfn2 is necessary for the maintenance of HSCs with lymphoid potential. Mechanistically, Mfn2 modulates calcium signalling to negatively regulate the transcription factor Nfat and sustains lymphoid lineages.
Haematopoietic stem cells (HSCs), which sustain production of all blood cell lineages
1
, rely on glycolysis for ATP production
2
,
3
, yet little attention has been paid to the role of mitochondria. Here we show in mice that the short isoform of a critical regulator of HSCs,
Prdm16
(refs
4
,
5
), induces mitofusin 2 (Mfn2), a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca
2+
, an effect mediated through its endoplasmic reticulum–mitochondria tethering activity
6
,
7
, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat). Nfat inhibition rescued the effects of
Mfn2
deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. These findings provide a mechanism underlying clonal heterogeneity among HSCs
8
,
9
,
10
,
11
and may lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation.
Journal Article
PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature
PRDM16 is a transcriptional coregulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes, and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling, and repressed inflammation, while sPrdm16 supported B cell development biased toward marginal zone B cells and induced an inflammatory signature. In a mouse model of human MLL-AF9 leukemia, fPrdm16 extended latency, while sPrdm16 shortened latency and induced a strong inflammatory signature, including several cytokines and chemokines that are associated with myelodysplasia and with a worse prognosis in human AML. Finally, in human NPM1-mutant and in MLL-translocated AML, high expression of PRDM16, which negatively impacts outcome, was associated with inflammatory gene expression, thus corroborating the mouse data. Our observations demonstrate distinct roles for Prdm16 isoforms in normal HSCs and AML, and identify sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.
Journal Article
A composite biomarker of neutrophil-lymphocyte ratio and hemoglobin level correlates with clinical response to PD-1 and PD-L1 inhibitors in advanced non-small cell lung cancers
Background
Immune checkpoint inhibitors (ICIs) have been incorporated into various clinical oncology guidelines for systemic treatment of advanced non-small cell lung cancers (aNSCLC). However, less than 50% (and 20%) of the patients responded to the therapy as a first (or second) line of therapy. PD-L1 immunohistochemistry (IHC) is an extensively studied biomarker of response to ICI, but results from this test have equivocal predictive power. In order to identify other biomarkers that support clinical decision-making around whether to treat with ICIs or not, we performed a retrospective study of patients with aNSCLC who underwent ICI-based therapy in the Mount Sinai Health System between 2014 and 2019.
Methods
We analyzed data from standard laboratory tests performed in patients as a part of the routine clinical workup during treatment, including complete blood counts (CBC) and a comprehensive metabolic panel (CMP), to correlate test results with clinical response and survival.
Results
Of 11,138 NSCLC patients identified, 249 had been treated with ICIs. We found associations between high neutrophil-to-lymphocyte ratio (NLR ≥ 5) and poor survival in ICI-treated NSCLC. We further observed that sustained high NLR after initiation of treatment had a more profound impact on survival than baseline NLR, regardless of PD-L1 status. Hazard ratios when comparing patients with NLR ≥ 5 vs. NLR < 5 are 1.7 (
p
= 0.02), 3.4 (
p
= 4.2 × 10
− 8
), and 3.9 (
p
= 1.4 × 10
− 6
) at baseline, 2–8 weeks, and 8–14 weeks after treatment start, respectively. Mild anemia, defined as hemoglobin (HGB) less than 12 g/dL was correlated with survival independently of NLR. Finally, we developed a composite NLR and HGB biomarker. Patients with pretreatment NLR ≥ 5 and HGB < 12 g/dL had a median overall survival (OS) of 8.0 months (95% CI 4.5–11.5) compared to the rest of the cohort with a median OS not reached (95% CI 15.9-NE,
p
= 1.8 × 10
− 5
), and a hazard ratio of 2.6 (95% CI 1.7–4.1,
p
= 3.5 × 10
− 5
).
Conclusions
We developed a novel composite biomarker for ICI-based therapy in NSCLC based on routine CBC tests, which may provide meaningful clinical utility to guide treatment decision. The results suggest that treatment of anemia to elevate HGB before initiation of ICI therapy may improve patient outcomes or the use of alternative non-chemotherapy containing regimens.
Journal Article
Analysis of Hypoxia and Hypoxia-Like States through Metabolite Profiling
In diverse organisms, adaptation to low oxygen (hypoxia) is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses.
Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases.
These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress.
Journal Article
An algorithm to identify patients aged 0–3 with rare genetic disorders
Background
With over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured electronic medical record data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. We sought to develop a digital phenotyping algorithm (
PheIndex
) using electronic medical records to identify children aged 0–3 diagnosed with genetic disorders or who present with illness with an increased risk for genetic disorders.
Results
Through expert opinion, we established 13 criteria for the algorithm and derived a score and a classification. The performance of each criterion and the classification were validated by chart review.
PheIndex
identified 1,088 children out of 93,154 live births who may be at an increased risk for genetic disorders. Chart review demonstrated that the algorithm achieved 90% sensitivity, 97% specificity, and 94% accuracy.
Conclusions
The
PheIndex
algorithm can help identify when a rare genetic disorder may be present, alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist.
Journal Article
Boris Choubert; unrecognized visionary geologist, pioneer of the global tectonics
This work is a review of Boris Choubert's paper (1935), which was published in French under the rather devalorizing title: \"Research on the Genesis of Palaeozoic and Precambrian Belts.\" Despite its innovative content, this article had no impact either at the time of its publication or even later. It begins with the construction of a remarkable fit of the circum-Atlantic continents. This was based on the -1.000 meters isobath instead of the shoreline. Thirty years before Bullard et al. (1965), it demonstrated in an indisputable way the reality of the continents motion on the surface of the Earth. Therefore, Choubert designated Wegener's \"continental drift\" as the main cause of tectonics. Even going beyond Wegener's theory, he argued that this mechanism was efficient well before the formation of the Triassic Pangaea, during the whole Palaeozoic to result in the building of the Caledonian and Hercynian mountains. Although he was still encumbered by the vocabulary of the time regarding geosynclines, Boris Choubert described tectonics based on the horizontal mobility of the Precambrian continental blocks. Oddly enough, he did not apply this model to the Precambrian structures, which he attributed to the effects of the Earth's rotation on the continental crust during its solidification. At the time of its publication, this paper was a very important step towards understanding global tectonics. Unfortunately, Choubert's contemporaries did not generally recognize its significance.
Journal Article
Petrogenesis of the peralkaline Flowers River Igneous Suite and its significance to the development of the southern Nain Batholith
The Flowers River Igneous Suite of north-central Labrador comprises several discrete peralkaline granite ring intrusions and their coeval volcanic succession. The Flowers River Granite was emplaced into Mesoproterozoic-age anorthosite–mangerite–charnockite–granite (AMCG) -affinity rocks at the southernmost extent of the Nain Plutonic Suite coastal lineament batholith. New U–Pb zircon geochronology is presented to clarify the timing and relationships among the igneous associations exposed in the region. Fayalite-bearing AMCG granitoids in the region record ages of 1290 ± 3 Ma, whereas the Flowers River Granite yields an age of 1281 ± 3 Ma. Volcanism occurred in three discrete events, two of which coincided with emplacement of the AMCG and Flowers River suites, respectively. Shared geochemical affinities suggest that each generation of volcanic rocks was derived from its coeval intrusive suite. The third volcanic event occurred at 1271 ± 3 Ma, and its products bear a broad geochemical resemblance to the second phase of volcanism. The surrounding AMCG-affinity ferrodiorites and fayalite-bearing granitoids display moderately enriched major- and trace-element signatures relative to equivalent lithologies found elsewhere in the Nain Plutonic Suite. Trace-element compositions also support a relationship between the Flowers River Granite and its AMCG-affinity host rocks, most likely via delayed partial melting of residual parental material in the lower crust. Enrichment manifested only in the southernmost part of the Nain Plutonic Suite as a result of its relative proximity to multiple Palaeoproterozoic tectonic boundaries. Repeated exposure to subduction-derived metasomatic fluids created a persistent region of enrichment in the underlying lithospheric mantle that was tapped during later melt generation, producing multiple successive moderately to strongly enriched magmatic episodes.
Journal Article