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Supplementary Figures S1-S11

Supplementary Tables S1-S19

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader ZBTB33 as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in patients with myelodysplastic syndrome. Zbtb33-edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and myelodysplastic syndromes.Significance:Mutations in known driver genes can be found in only about half of individuals with clonal hematopoiesis. Here, we performed a somatic mutation discovery effort in nonmalignant blood samples, which identified novel candidate genes that may play biological roles in hematopoietic stem cell expansion and hematologic malignancies.This article is highlighted in the In This Issue feature, p. 403

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non–B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non–recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.Significance:Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies.This article is highlighted in the In This Issue feature, p. 171

Supplementary Figure from Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19

La falla Cerritos pertenece a la porción oeste del Sistema de Fallas Morelia-Acambay, ubicada al suroeste de la ciudad de Morelia, en el estado de Michoacán, México; es una zona con alta densidad de fallas activas con geometrías segmentadas y arreglos en échelon, donde se han desarrollado semi-grabens y grabens de dimensiones variables que inclusive influyen en el alineamiento y distribución del vulcanismo monogenético holocénico. En la superficie, estas fallas afectan unidades litológicas de edades miocénicas hasta suelos modernos. Debido a la peligrosidad sísmica que se ha reportado para algunas de las fallas de Morelia, se realizó un análisis interdisciplinario de la falla Cerritos, que había permanecido poco estudiada hasta la fecha. La falla Cerritos es una falla normal con una ligera componente lateral izquierda, una longitud de 12 km y un relieve topográfico bien definido de 130±5 m (100 m de desplazamiento visible + 30 m de desplazamiento subsuperficial obtenido por el estudio de resistividad invertida). Esta falla muestra un rumbo ENE-OSO (255°) y un echado de 76° hacia el NNO. En un afloramiento de la falla Cerritos, a unos cuantos metros del trazo de falla principal, se identificó una cuña coluvial con abundante materia orgánica, fechada con el método de radiocarbono en 3.37–3.21 cal ka AP. El análisis geológico y geomorfológico de la falla reveló que es una estructura tectónicamente activa, relativamente joven y con índices geomórficos que indican mayor actividad en su sector oriental. El escarpe y la acumulación de sedimentos lacustres en el bloque caído sugieren movimiento activo vertical (levantamiento y subsidencia, respectivamente) a lo largo de esta falla. Los resultados obtenidos mediante los análisis de sísmica de refracción, tomografía de resistividad eléctrica y magnetometría terrestre revelaron la geometría de la falla en profundidad, en donde sobresale la presencia de un plano principal lístrico y una zona de deformación en el bloque caído que se extiende en superficie hasta 75 m desde el pie del escarpe principal. Esta zona de deformación se caracteriza por la formación de anticlinales tipo roll-over y dos grabens de colapso crestal delimitados por estructuras secundarias, los cuales funcionan como depocentros de materiales clásticos y bloques caídos. Finalmente, el análisis de actividad y potencialidad indicó que esta estructura tiene tasas de desplazamiento de 0.03±0.01 mm/año, con desplazamientos verticales promedio de 0.5 m por evento, y un tiempo de recurrencia promedio de 16700 años. La Falla Cerritos tiene la capacidad de producir eventos de ruptura con magnitudes de Mw 6.2 a 6.6 por sí sola, o bien, puede interaccionar en un evento extremo con las fallas adyacentes Morelia y Cointzio, produciendo eventos de ruptura multi-falla con magnitudes de hasta Mw 6.9.

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

In this study, three geophysical techniques were used to identify, localize, and characterize a partly blind fault in the Llano Grande basin within the Agua Fría Graben. This tectonic basin is located in the Los Azufres Volcanic Complex, one of the major silicic volcanic centers in the Trans-Mexican Volcanic Belt. The 1 km wide Agua Fría graben could be considered as an analogous of the larger graben structures bounded by the Morelia-Acambay Fault System. Since it is filled by recent sediments, it represents a challenge for the recognition and characterization of active faults that lack clear surface expression. Newly collected magnetic data led to the identification of lineaments interpreted as structural discontinuities. Ground penetrating radar and seismic refraction surveys were carried out across one of these magnetic lineaments crossing the basin to characterize the nature and geometry of the inferred discontinuity. The ground penetrating radar profiles allowed the identification of buried deformational structures interpreted as the northern segment of the Agua Fría fault. The subsurface reflectors displaced 1 to 1.5 m by the fault indicate that this structure is potentially active. The opening of trenches based on these results makes it possible to confirm the interpretation of the geophysical profiles, to discuss the precision of the data and to validate their use for such studies. On seismic refraction profiles, the deformation zones are related to low P-wave velocity zones. These geophysical studies demonstrate the potential of such techniques to locate faults in the subsurface, partially characterize the width of the fault zone and the associated displacement within the uppermost of the subsurface. Our results may be applied to define ideal sites for paleoseismic excavations which are essential for the identification and description of historical and prehistoric earthquakes, and thus, for the characterization of the local seismic hazard.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.

Papillary breast lesions are a heterogeneous group of neoplasms of diverse imagenological, clinical and morphological presentation that display different behaviour, prognosis and, therefore, controversial diagnosis and management. The aim of this study is to propose an algorithm for the management of mammary lesions. Materials and methods We show a retrospective review of breast imaging reporting, percutaneous needle biopsy information, histological-pathological reports and subsequent management. Results A total of 7,920 biopsies were reviewed. Only 136 biopsies from 130 patients with papillary lesions met the inclusion criteria. There was a correlation between the pathologic findings from percutaneous biopsy and the final surgical histologic result in patients with surgery recommendation in all but 2 (2.12%) cases in which the surgery results were upgraded to a malignant disease. Conclusions The algorithm proposed in this paper for the management of mammary lesions significantly reduces the possibilities of upgrading and favours decision making between follow-ups or surgery in patients with papillary lesions of the breast.

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2V617F-expressing neutrophils and that PAD4 is required for Jak2V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2 mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of Setd2 in a murine model decreased the latency of MLL-AF9-induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish SETD2 alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target SETD2-mutant leukemias.