Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal ...hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to ...leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.
•Hematopoietic stem/progenitor mutation burden is not increased in SCN.•Clonal hematopoiesis due to mutations of TP53 is present in the majority of patients with SDS.
Loss of chromosome 7 has long been associated with adverse-risk myeloid malignancy. In the last decade, CUX1 has been identified as a critical tumor suppressor gene (TSG) located within a commonly ...deleted segment of chromosome arm 7q. Additional genes encoded on 7q have also been identified as bona fide myeloid tumor suppressors, further implicating chromosome 7 deletions in disease pathogenesis. This review will discuss the clinical implications of del(7q) and CUX1 mutations, both in disease and clonal hematopoiesis, and synthesize recent literature on CUX1 and other chromosome 7 TSGs.
Two major studies, including a new mouse model, have been published that support a role for CUX1 inactivation in the development of myeloid neoplasms. Additional recent studies describe the cellular and hematopoietic effects from loss of the 7q genes LUC7L2 and KMT2C/MLL3, and the implications of chromosome 7 deletions in clonal hematopoiesis.
Mounting evidence supports CUX1 as being a key chromosome 7 TSG. As 7q encodes additional myeloid regulators and tumor suppressors, improved models of chromosome loss are needed to interrogate combinatorial loss of these critical 7q genes.
Hematopoietic stem cells (HSCs) sustain lifelong, multipotent output, however, the molecular mechanisms governing HSC homeostasis remain unclear. Elucidating this process is key to understanding the ...imbalanced differentiation and self-renewal evident in myeloid malignancies. CUX1 is a transcription factor that is monoallelically mutated or deleted in high-risk myeloid malignancies. We previously reported that CUX1 has critical, dose-dependent roles in hematopoiesis and myeloid neoplasia. The haploinsufficient nature of CUX1 in myeloid neoplasia and the broad dose-dependent requirement of CUX1 in hematopoiesis led us investigate the role of CUX1 in earliest stages of hematopoiesis. We generated a CUX1 reporter mouse in which mCherry is fused in-frame with the C-terminus of CUX1 to study how the level of CUX1 in HSCs affects their behavior. Overall, we find that CUX1 protein levels within the HSC compartment delineates stem cell activity. Stringently defined immunophenotypic HSCs with low CUX1 levels (CUX1 Dim) are phenotypically dormant, as assessed by transcriptional profiling and proliferation assays, as opposed to CUX1 Bright HSCs which have greater cell cycle participation. In transplantation assays, CUX1 Dim HSCs are initially platelet-biased but give rise to long-term, multilineage reconstitution. CUX1 Bright HSCs are initially erythroid-biased but lack long-term HSC activity and the capacity for self-renewal. In other words, despite immunophenotypic HSC markers, CUX1 Bright HSCs are not, by definition, HSCs. By most metrics, CUX1 Intermediate HSCs exhibit a distinct, albeit intermediate, phenotype. Therefore, along a continuous gradient of CUX1 expression, HSCs gradually lose the ability to self-renew as CUX1 expression increases. Remarkably, knockdown of CUX1 in CUX1 Bright HSCs re-endows these cells with the capacity for long-term multilineage chimerism, suggesting low levels of CUX1 are required for stem cell activity in HSCs. Inversely, overexpression of CUX1 in HSCs promotes their expansion and ultimate exhaustion, further demonstrating that the level of CUX1 controls HSC fate. Altogether, we report that low CUX1 levels are required for HSC self-renewal and implicate CUX1 as a molecular rheostat for HSC behaviors such as cell division and differentiation. Further, we describe an unprecedented capacity for cells without demonstrated HSC activity to acquire HSC capacity and a novel role for CUX1 in preventing this plasticity.
This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).
This single arm, multicentre phase II trial ...enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.
The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.
Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.
In Vietnam, the middle class is expected to grow from 12 million to 33 million people between 2012 and 2020. The growth causes an increase as well as a shift in consumption. Products that were not ...accessible or affordable before will become increasingly so, such as cars, dishwashers, meat products and air-conditioning. In urban areas the changes are most prominent and so are the side effects: increased amounts of waste, smog, pollution and use of fossil energy or pesticides.
The main objective of this study was to identify sustainable behaviour that followed or did not follow from the intervention project GetGreen Vietnam. 604 urban middle class consumers participated in a series of sustainable consumption trainings. Before, during and after the trainings, quantitative and qualitative data was collected on 90 sustainable actions.
64% of the participants self-reported to be engaged in a sustainable action before the intervention and this percentage increased to 80% after. The group environment and activity-based meetings of GetGreen Vietnam project (GGVN) were critical for the success of the intervention. Participants reported that before GGVN certain actions were already habitual as a money saving strategy (e.g. sparse electricity use or food leftovers re-use) or due to past scarcity (e.g. sparse water use). Many participants reported the intention to buy sustainable products but fewer participants took action to do so.
A powerful strategy toward more sustainable consumption in Vietnam can be to create more group-based activities around the themes of energy and shopping for food. A twofold approach is needed that both installs new sustainable consumption patterns and keeps old habits rooted in daily rituals. Role models should set an example for the young population and consumers and (Vietnamese) producers should be better connected to increase mutual trust and transparency.
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