Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5.

A fundamental property of leukemic stem cells is clonal dominance of the bone marrow microenvironment. Truncation mutations of CSF3R, which encodes the G-CSF receptor (G-CSFR), are implicated in leukemic progression in patients with severe congenital neutropenia. Here we show that expression of a truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level that is dependent upon exogenous G-CSF. G-CSF-induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r. Conversely, the proliferative advantage conferred by the mutant Csf3r was abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and HSC function was reduced in mice expressing a truncated mutant Csf3r engineered to have impaired Stat5 activation. These data indicate that in mice, inappropriate Stat5 activation plays a key role in establishing clonal dominance by stem cells expressing mutant Csf3r.

Similarities and disparities in cancer burden among Arab world females.

INTRODUCTION: Cancer is the leading cause of increased morbidity and mortality worldwide. This work aims to study the Arab-world females' cancers (AFCs), the similarities and disparities from epidemiological, economic and development-indices points of view. MATERIALS AND METHODS: Descriptive - Analytical review of the 2018 Global Cancer Observatory concerning AFCs. Data on various cancers were compiled and compared among the countries in the regions and the world females' cancers (WFCs). RESULTS: A total estimate of 227,494 new AFCs; 2.64% of WFCs, with an average crude incidence rate of 111.7* and an age-standardized rate of 134.5*, compared to 228* and 182.6* of WFCs, respectively. Death cases estimated to be 122,903; 2.95% of WFCs, with an average crude mortality rate of 60.3* and age-standardizedrate of 75.4*, compared to 110.2* and 83.1* of WFCs, respectively. Five-year prevalent cases were 530,735; 2.33% of WFCs, with an average proportion of 260.5*, compared to 603.5* of WFCs. Mortality to Incidence Ratio was 0.54 (range 0.36 - 0.80), compared to 0.58, 0.52, 0.49 in the medium human development index, upper-middle-income countries and world countries, respectively. */100,000 population. CONCLUSIONS: Despite the demographic and cultural similarities among the Arab communities, there are apparent disparities in AFCs. A systematic approach is required to address these remarkable differences in cancer ranking and rates among Arab countries themselves and when compared to other world groups and nations.

PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

Use of [18F]fluorodeoxyglucose positron emission tomography in evaluating locally recurrent and metastatic adrenocortical carcinoma.

CONTEXT: Adrenocortical carcinomas are uncommon, and their evaluation by [(18)F]fluorodeoxyglucose positron emission tomography (FDG PET) has not been well evaluated. OBJECTIVE: The purpose of this study was to examine the potential utility of FDG PET in the detection of recurrent or metastatic adrenocortical carcinoma. DESIGN: In patients with known adrenocortical carcinoma who underwent FDG-PET imaging for suspected recurrence or metastasis, FDG activity was compared with other imaging findings, clinical features, and the presence or absence of disease as confirmed by resection, biopsy, or clinical follow-up. SETTING: The study took place at four tertiary referral centers. PATIENTS OR OTHER PARTICIPANTS: Twelve patients (10 females and two males, 5-71 yr of age) were evaluated. MAIN OUTCOME MEASURES: The main outcome measures were FDG activity, other imaging findings, and clinical features. RESULTS: Abnormal FDG uptake correctly indicated tumor recurrence in 10 patients. One patient with no abnormal FDG activity had a morphological abnormality subsequently proven to be a postoperative scar. Two patients, one with very small pulmonary lesions and one with a hepatic metastasis, had false-negative findings. CONCLUSIONS: Most adrenocortical carcinomas accumulate and retain FDG and thus can be visualized by PET. However, false-negative findings are possible, especially with very small lesions.

A truncation mutant of Csf3r cooperates with PML-RARα to induce acute myeloid leukemia in mice.

Severe congenital neutropenia is associated with a marked propensity to develop myelodysplasia or acute myeloid leukemia (AML). Truncation mutations of CSF3R, encoding the granulocyte colony-stimulating factor receptor (G-CSFR), are associated with development of myelodysplasia/AML in severe congenital neutropenia. However, a causal relationship between CSF3R mutations and leukemic transformation has not been established. Herein, we show that truncated G-CSFR cooperates with the PML-RARα oncogene to induce AML in mice. Expression of truncated G-CSFR significantly shortens the latency of AML in a G-CSF-dependent fashion and it is associated with a distinct AML presentation characterized by higher blast counts and more severe myelosuppression. Basal and G-CSF-induced signal transducer and activator of transcription 3, signal transducer and activator of transcription 5, and extracellular signal-regulated kinase 1/2 phosphorylation were highly variable but similar in leukemic blasts expressing wild-type and truncated G-CSFR. These data provide new evidence suggesting a causative role for CSF3R mutations in human AML.

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia.

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.