The growth of malignant cells is not only driven by cell-intrinsic factors, but also by the surrounding stroma. Monocytes/Macrophages play an important role in the onset and progression of solid ...cancers. However, little is known about their role in the development of acute myeloid leukemia, a malignant disease characterized by an aberrant development of the myeloid compartment of the hematopoietic system. It is also unclear which factors are responsible for changing the status of macrophage polarization, thus supporting the growth of malignant cells instead of inhibiting it. We report herein that acute myeloid leukemia leads to the invasion of acute myeloid leukemia-associated macrophages into the bone marrow and spleen of leukemic patients and mice. In different leukemic mouse models, these macrophages support the in vitro expansion of acute myeloid leukemia cell lines better than macrophages from non-leukemic mice. The grade of macrophage infiltration correlates in vivo with the survival of the mice. We found that the transcriptional repressor Growth factor independence 1 is crucial in the process of macrophage polarization, since its absence impedes macrophage polarization towards a leukemia supporting state and favors an anti-tumor state both in vitro and in vivo These results not only suggest that acute myeloid leukemia-associated macrophages play an important role in the progression of acute myeloid leukemia, but also implicate Growth factor independence 1 as a pivotal factor in macrophage polarization. These data may provide new insights and opportunities for novel therapies for acute myeloid leukemia.
Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting ...histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as ...myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of
in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of
, and latency was further decreased when
was conditionally deleted. Loss of
significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of
led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.
The differentiation of haematopoietic cells is regulated by a plethora of so-called transcription factors (TFs). Mutations in genes encoding TFs or graded reduction in their expression levels can ...induce the development of various malignant diseases such as acute myeloid leukaemia (AML). Growth Factor Independence 1 (GFI1) is a transcriptional repressor with key roles in haematopoiesis, including regulating self-renewal of haematopoietic stem cells (HSCs) as well as myeloid and lymphoid differentiation. Analysis of AML patients and different AML mouse models with reduced GFI1 gene expression levels revealed a direct link between low GFI1 protein level and accelerated AML development and inferior prognosis. Here, we report that upregulated expression of GFI1 in several widely used leukemic cell lines inhibits their growth and decreases the ability to generate colonies in vitro. Similarly, elevated expression of GFI1 impedes the in vitro expansion of murine pre-leukemic cells. Using a humanized AML model, we demonstrate that upregulation of GFI1 expression leads to myeloid differentiation morphologically and immunophenotypically, increased level of apoptosis and reduction in number of cKit
cells. These results suggest that increasing GFI1 level in leukemic cells with low GFI1 expression level could be a therapeutic approach.
To understand the burden associated with pediatric chronic pain (CP) on the health care system compared with other costly chronic diseases prior to subspecialty care.
In this retrospective cohort ...study, we assessed all-cause health care utilization and direct health care costs associated with pediatric CP (n = 91) compared with juvenile arthritis (n = 135), inflammatory bowel disease (n = 90), type 1 diabetes (n = 475) or type 2 diabetes (n = 289), anxiety (n = 7193), and controls (n = 273) 2 and 5 years prior to patients entering subspecialty care in Manitoba, Canada. Linked data from physician encounters, emergency department visits, hospitalizations, and prescriptions were extracted from administrative databases. Differences in health care utilization and direct health care costs associated with CP vs the other conditions were tested using negative binomial and zero-inflated negative binomial regression models, respectively.
After adjustment for age at diagnosis, sex, location of residence, and socioeconomic status, CP continued to be associated with the highest number of consulted physicians and subspecialists and the highest number of physician billings compared with all other conditions (P < .01, respectively). CP was significantly associated with higher physician costs than juvenile arthritis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, or controls (P < .01, respectively); anxiety was associated with the highest physician and prescription costs among all cohorts (P < .01, respectively).
Compared with chronic inflammatory and endocrinologic conditions, pediatric CP and anxiety were associated with substantial burden on the health care system prior to subspecialty care, suggesting a need to assess gaps and resources in the management of CP and mental health conditions in the primary care setting.
Background:
Growth factor independence 1 (GFI1) is a transcriptional repressor, which regulates the proliferation and differentiation of hematopoietic stem cells. We have previously shown that lower ...expression of GFI1 promotes the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients and murine models of leukemiua. Additionally, a germline single nucleotide polymorphism variant of GFI1, called GFI1–36N (Ser36 replaced by Asn36) contributes to the development of MDS and AML. Both lower expression of GFI1 and presence of GFI1–36N leads to expression of a number key AML associated oncogenes and signaling cascades promoting AML development, as low level of GFI1 or GFI1–36N are not able to repress these patways. Aorund 30% of all AML patients have either low expression levels of GFI1 or are carrier of GFI1–36N. This patient cohort has a particular poor prognosis. However, we also have preliminary data that GFI1 might be involved in DNA repair.
Aims:
We analyzed whether GFI1 plays a role in DNA repair.
Methods:
We analyzed genome wide mutational analysis from AML patient cohorts and gene wide expression data.
Results:
We reanalyzed available genomic data of MDS/AML patients with expression of GFI1–36N or low expression of GFI1. These patients showed significantly more cytogenetic aberrations than patients with normal level of GFI1–36S. We have established two different mouse strains, which express either low level of GFI1 or express GFI1–36N. In murine models of human AML, low level of GFI1 or expression of GFI1–36N led to a significantly higher rate of genomic alterations such as mutations, deletions and insertions than GFI1 wildtype (wt) expressing murine leukemic cells. These findings indicate that low expression of GFI1 or expression of GFI1–36N is associated with genomic instability. To understand the molecular pathways GFI1 is involved with regad to DNA repair, we irradiated GFI1 wt, GFI1 low expressing and GFI1–36N expressing thymocytes. Using comet and γH2AX assay we showed that presence of Gfi1–36N or reduced level of GFI1 is associated with diminished DNA repair. Furthermore we found that presence of GFI136N or reduced level of GFI1 is associated with low level of MGMT. Other groups have shown that patients with low expression of MGMT respond well to treatment with Temozolomide (alkylating agent). Due to this fact we treated leukemic cells differently expressing GFI1 with Temozolomide. We found that the leukemic cells with low level of GFI1 or GFI1–36N are highly susceptible to Temozolomide compared to the leukemic control cells.
Summary/Conclusion:
In summary, low expression of GFI1 or expression of GFI1–36N leads to a clonal genetic evolution by impeding DNA repair. Therefore GFI1 could be a new target in leukemia therapy by using Temozolomide for these patients.
Bituminous shales of the Late Jurassic Madbi Formation from Shabwah depression in the south-eastern Sabatayn Basin has been collected and analyzed. The organofacies, paleo-sedimentary environmental ...conditions and oil generation potential are discussed based on combined geochemistry and petrology investigations. Biomarkers indicate that the bituminous-analyzed shales contain mainly marine phytoplankton algae and minor land plants and deposited under reducing environmental conditions. The rich in lipids from phytoplankton algae and land plants suggest high Type II to mixtures of Types II and Type III kerogen as the original organic facies during deposition. This is consistent with significant amounts of alginite and amorphous organic matter, with minor vitrinite land plants observed under microscope and hydrogen index (HI) values of 210–679 mg HC per g TOC and indicated good to excellent oil-source rocks. The presence of the reducing conditions during deposition consequently enhanced the preservation and subsequently gave rise to enrichment of organic matter in the analyzed bituminous shale as indicated by the relatively high TOC values between 1 and 14 wt%.
The geochemical maturity indicators show that the analyzed bituminous shales have reached a low maturity stage, and commercial oils have not yet generated. Therefore, the results presented and discussed in this study suggest that the low maturity bituminous shales can be heated to crack the kerogens and subsequently significant amount of oil can be generated. This will lead to a huge alternative potential of unconventional resources and provide a sense of extending the exploration activities for both unconventional and conventional petroleum resources in the whole Basin.
•Late Jurassic bituminous shales existed in the Shabwah depression were collected and analyzed.•The bituminous shales from Shabwah depression contain mainly Type II and mixture II and III kerogens.•The shales contain mainly phytoplankton algae and land plants and deposited under reducing conditions.•These shales are at low maturity of oil-generation, thus, they are useful for an unconventional oil shale exploration.
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