Leukemia In Man Research Articles

Abstract A013: Sex-dependent hematopoietic stem cell aging and leukemogenic potential

Abstract Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders. But how HSC aging and sex co-influence leukemogenesis is poorly understood. By examining HSC aging in young, aging (75% lifespan) and longevity (110% lifespan) mice in males vs females, we have discovered that aging males have a significantly higher HSC frequency than females, and that male HSC aging is characterized by an expansion of Lin-CD150+SP HSCs and a decrease of Lin-CD150-SP HSCs, whereas females show opposite HSC changes towards aging and longevity. In line with HSC changes, aging males exhibit an increase of white blood cell counts that is primarily driven by increased myeloid cells, whereas aging females shows a decrease of white blood cell counts that is primarily driven by reduced lymphoid cells. To understand leukemogenic potential of aging HSCs in the true setting of organismal aging, we generated the first aging mouse model of chronic myeloid leukemia (CML) induced by BCR-ABL1 (Oncogene, 2021, 40: 3152-3163). We found that aging male HSCs are significantly more susceptible to BCR-ABL1 transformation and CML induction in aging male mice than aging female HSCs for CML induction in aging female mice. However, in the absence of oncogenic translocation genes, longevity female but not male mice rapidly develop B/myeloid mixed phenotype acute leukemia, a disease of HSC origin, in primary bone marrow transplantation recipients. Leukemias in our aging mouse models phenocopy those of humans in that the incidence of myeloid leukemia is higher in aging men than in women overall, but longevity women have a higher incidence of myeloid leukemia. Using single cell RNA sequencing analysis of HSCs, we found distinct cell clustering patterns and signaling pathways of aging HSCs between male and female mice. The top pathways seen in male HSC aging involve TGFβ and TNFα signaling that have been linked to poor drug response and persistence of human CML stem cells, while those for female HSC aging involve IFNα/γ signaling pathways that have been associated with good drug response of human CML stem cells. Together, our results demonstrate sex-dependent HSC aging and leukemogenic potential and that molecular changes in aging HSCs can inform drug response of leukemia stem cells. Our findings provide novel insight into the etiology of leukemia in males vs females and suggest potential benefit to use sex-based prevention and therapeutic strategies for leukemia in men vs women. Citation Format: WenYong Chen. Sex-dependent hematopoietic stem cell aging and leukemogenic potential [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A013.

Comparative analysis of the associations between solar activity and trends in the incidence of haemoblastoses in Russia, the USA and Canada

Background. Identification of the links between hemoblastoses and environmental factors is necessary for the development of preventive measures.
 Aim. Comparative analysis of the link between hemoblastosis trends in Russia, the USA and Canada and solar activity.
 Material and methods. The open data on the incidence of hemoblastoses in Canada (19832012), the USA (19982012) and Russia (19932018) was used. To estimate solar activity, the average annual number of sunspots (Wolff numbers) was taken. The relationship between the frequency of hemoblastoses and solar activity was studied using the Pearson correlation analysis in 11 iterations (lag 010 years). The results obtained are compared with the data of an earlier study on Russia.
 Results. In Canada, an association with Wolf numbers was found in the frequency of Hodgkin's lymphoma in men (r=0.431, p=0.017, lag 2 years), multiple myeloma in women (r=0.542, p=0.037, lag 1 year), non-Hodgkin's lymphomas in men (r =0.538, p=0.038, lag 5 years) and women (r=0.750, p=0.001, lag 5 years), leukemia in men (r=0.707, p=0022, lag 7 years) and women (r=0.817, p=0.004, lag 7 years). In the United States, a relationship with solar activity was established for fluctuations in the incidence of Hodgkin's lymphoma in men (r=0.577, p=0.050, lag 5 years) and women (r=0.641, p=0.025, lag 5 years), non-Hodgkin's lymphomas in men (r=0.809, p 0.001, lag 3 years) and women (r=0.844, p 0.001, lag 2 years), leukemia in men (r=0.619, p=0.032, lag 1 year). In the Russian population, a relationship between solar activity and the frequency of all forms of hemoblastoses, was previously revealed. Fluctuations in the frequency of leukemia and non-Hodgkin's lymphomas in the populations of Russia, the USA and Canada have a strong positive relationship with solar activity. The strength of this association in Hodgkin's lymphoma and multiple myeloma ranges from moderate to significant. In all the countries studied, an increase in the incidence of multiple myeloma and leukemia was found, and an increase in the incidence of non-Hodgkin's lymphomas was found in Russia and Canada. The trend in the incidence of Hodgkin's lymphoma in Russia and Canada has a significant downward trend.
 Conclusion. Trends in hemoblastoses in Russia, the USA and Canada are strongly related to solar activity.

Evolution of socioeconomic inequalities in cancer incidence between 2006 and 2016 in France: a population-based study.

The existence of socioeconomic inequalities in cancer incidence is now well established and their reduction is a priority in many countries. This study aimed to measure the evolution of socioeconomic inequalities in the incidence of the most common cancers in France, over an 11-year period. The study focused on 19 cancer entities (16 solid tumors and 3 hematological malignancies). Data are obtained from the French Network of Cancer Registries, representing 604 205 cancer cases. Each patient address was geolocalized and assigned to an IRIS, the smallest geographic unit in France. The French version of the European Deprivation Index was used to measure the level of deprivation in each IRIS. A generalized linear mixed model was used to account for the longitudinal nature of the data and to assess the evolution of socioeconomic inequalities. A significant evolution of the social gradient of incidence over time was highlighted for five cancer entities and all entities combined. For lung cancer for both sexes and bladder cancer in men, more frequent in deprived areas, the social gradient in incidence tended to decrease over time. For breast cancer in women and lymphocytic leukemia in men, more frequent in affluent areas, the gap continues to widen. Cancer entities with large disparities continued to present social inequalities in incidence without exacerbation with time. The few temporal evolutions observed do not show a worsening of the social gradient of incidence to the disadvantage of the most deprived areas, but rather an increase in incidence that is greater in the most affluent areas.

Metagenomic discovery and functional validation of L-asparaginases with anti-leukemic effect from the Caspian Sea.

SummaryBy screening 27,000 publicly available prokaryotic genomes, we recovered ca. 6300 type I and ca. 5200 type II putative L-asparaginase highlighting the vast potential of prokaryotes. Caspian water with similar salt composition to the human serum was targeted for in silico L-asparaginase screening. We screened ca. three million predicted genes of its assembled metagenomes that resulted in annotation of 87 putative L-asparaginase genes. The L-asparagine hydrolysis was experimentally confirmed by synthesizing and cloning three selected genes in E. coli. Catalytic parameters of the purified enzymes were determined to be among the most desirable reported values. Two recombinant enzymes represented remarkable anti-proliferative activity (IC50 <1IU/ml) against leukemia cell line Jurkat while no cytotoxic effect on human erythrocytes or human umbilical vein endothelial cells was detected. Similar salinity and ionic concentration of the Caspian water to the human serum highlights the potential of secretory L-asparaginases recovered from these metagenomes as potential treatment agents.

A cohort study of banana plantation workers in the French West Indies: first mortality analysis (2000-2015).

Chlordecone, an organochlorine insecticide, was widely used in the French West Indies banana plantations. We set up a cohort of banana plantation workers who worked between 1973 and 1993, the period of authorized use of chlordecone. Vital status and causes of death were collected from French national registries. Workers were followed up from 1 January 2000 to 31 December 2015. Cause-specific mortality in the cohort was compared to that of the general population of the French West Indies by computing standardized mortality ratios (SMRs). A total of 11,112 workers (149,526 person-years, 77% men) were included in the mortality analysis, and 3647 deaths occurred over the study period. There was a slight deficit in all-cause mortality, which was statistically significant in men (SMR = 0.93, 95% CI 0.89-0.96), but not in women (SMR = 0.96, 95% CI 0.89-1.04). All-cancer mortality did not differ significantly from that of the general population (men: SMR = 0.96, 95% CI 0.90-1.03; women: SMR = 1.04, 95% CI 0.89-1.21). Significant excesses of deaths were observed for stomach cancer in women (SMR = 1.94, 95% CI 1.24-2.89) and pancreatic cancer in women farm owners (SMR = 2.31, 95% CI 1.06-4.39). Mortality from prostate cancer was similar to that of the general population in the whole cohort (SMR = 1.00; 95% CI 0.89-1.13) and non-significantly elevated among farm workers (SMR = 1.10, 95% CI 0.87-1.36). Non-significant increases in mortality were also observed for lung cancer in women, leukemia in men, and non-Hodgkin lymphoma in both genders.

Basal cell skin cancer and the risk of second primary cancers: a cancer registry–based study in Lithuania

PurposeThe aim of this population-based cohort study was to determine the risk of second primary cancer in basal cell carcinoma (BCC) patients in Lithuania. MethodsThis analysis was based on patients diagnosed with BCC in Lithuania between 1998 and 2007 and followed until 2011. Standardized incidence ratios for subsequent cancers as a ratio of observed number of cancer cases in people with previous BCC diagnosis to the expected number of cancer cases in the underlying general population were calculated. ResultsAfter diagnosis of BCC, 1442 new cases of selected cancers were diagnosed. Compared with the general population, the incidence of all new primaries combined after BCC was very close to expected. Statistically meaningful increase in developing subsequent cancer was obtained for Hodgkin's lymphoma, prostate cancer, and leukemia in men, and for cancers of the lip, lung, and breast in women. Risk of melanoma and thyroid cancer was significantly elevated in both sexes. Relative risk of cancer of the eye was increased although not significant. ConclusionsIn our study, we found increased cancer risk for cancers related to sun exposure. In addition, increased risks were identified for Hodgkin's lymphoma, thyroid cancer, leukemia, prostate, and breast cancer in BCC patients.

A topographical study of leukemia in man and cattle in Denmark.

A topographical study of leukemia in man and cattle in Denmark.

Hepatitis E and Lymphocytic Leukemia in Man, Italy

Hepatitis E and Lymphocytic Leukemia in Man, Italy

Ecological Study on Hospitalizations for Cancer, Cardiovascular, and Respiratory Diseases in the Industrial Area of Etang-de-Berre in the South of France

The Etang-de-Berre area is a large industrialized area in the South of France, exposing 300,000 inhabitants to the plumes of its industries. The possible associated health risks are of the highest concern to the population, who asked for studies investigating their health status. A geographical ecological study based on standardized hospitalizations ratios for cancer, cardiovascular, and respiratory diseases was carried out over the 2004–2007 period. Exposure to air pollution was assessed using dispersion models coupled with a geographic information system to estimate an annual mean concentration of sulfur dioxide (SO2) for each district. Results showed an excess risk of hospitalization for myocardial infarction in women living in districts with medium or high SO2 exposure, respectively, 38% [CI 95% 4 : 83] and 54% [14 : 110] greater than women living in districts at the reference level exposure. A 26% [2 : 57] excess risk of hospitalization for myocardial infarction was also observed in men living in districts with high SO2 levels. No excess risk of hospitalization for respiratory diseases or for cancer was observed, except for acute leukemia in men only. Results illustrate the impact of industrial air pollution on the cardiovascular system and call for an improvement of the air quality in the area.

Consumption of artificial sweetener– and sugar-containing soda and risk of lymphoma and leukemia in men and women

Despite safety reports of the artificial sweetener aspartame, health-related concerns remain. We prospectively evaluated whether the consumption of aspartame- and sugar-containing soda is associated with risk of hematopoetic cancers. We repeatedly assessed diet in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). Over 22 y, we identified 1324 non-Hodgkin lymphomas (NHLs), 285 multiple myelomas, and 339 leukemias. We calculated incidence RRs and 95% CIs by using Cox proportional hazards models. When the 2 cohorts were combined, there was no significant association between soda intake and risks of NHL and multiple myeloma. However, in men, ≥1 daily serving of diet soda increased risks of NHL (RR: 1.31; 95% CI: 1.01, 1.72) and multiple myeloma (RR: 2.02; 95% CI: 1.20, 3.40) in comparison with men who did not consume diet soda. We observed no increased risks of NHL and multiple myeloma in women. We also observed an unexpected elevated risk of NHL (RR: 1.66; 95% CI: 1.10, 2.51) with a higher consumption of regular, sugar-sweetened soda in men but not in women. In contrast, when sexes were analyzed separately with limited power, neither regular nor diet soda increased risk of leukemia but were associated with increased leukemia risk when data for men and women were combined (RR for consumption of ≥1 serving of diet soda/d when the 2 cohorts were pooled: 1.42; 95% CI: 1.00, 2.02). Although our findings preserve the possibility of a detrimental effect of a constituent of diet soda, such as aspartame, on select cancers, the inconsistent sex effects and occurrence of an apparent cancer risk in individuals who consume regular soda do not permit the ruling out of chance as an explanation.

Association between drinking water uranium content and cancer risk in Bavaria, Germany

To evaluate the possible association between uranium (U) content in public drinking water on the one hand and the risk of cancer of the colorectum, lung, female breast, prostate, kidney, and urinary bladder, total cancer, and leukemia on the other hand in Bavaria, an ecologic study on the level of municipalities was performed. Cancer incidence data for the years 2002-2008 were obtained from the population-based cancer registry Bavaria according to sex. Current U content data of public drinking water on the level of municipalities were obtained from a publicly available source. The possible association between drinking water U content and cancer risk adjusted for average socio-economic status was evaluated using Poisson regression. Drinking water U content was below 20 μg/L in 458 out of 461 included municipalities. We found a significantly increased risk of leukemia in men in the intermediate (U level, 1.00-4.99 μg/L; relative risk [RR], 1.14) and in the highest U exposure category (U level, ≥5 μg/L; RR, 1.28). Moreover, in women, a significantly elevated risk was identified with respect to kidney cancer in the highest exposure category (RR, 1.16) and with respect to lung cancer in the intermediate exposure category (RR, 1.12). The slightly increased risk of leukemia in men, kidney cancer in women, and lung cancer in women may require further investigation. If an increased cancer risk is confirmed, preventive measures (e.g., introduction of U filters in public water systems) may be considered.

Smoking at diagnosis and survival in cancer patients

The effect of smoking on survival in cancer patients is limited by the lack of structured prospective assessments of smoking at diagnosis. To assess the effect of smoking at diagnosis on survival, structured smoking assessments were obtained in a cohort of 5,185 cancer patients within 30 days of a cancer diagnosis between 1982 and 1998. Hazard ratios (HRs) or odds ratios were generated to analyze the effects of smoking at diagnosis on overall mortality (OM) and disease-specific mortality (DSM) in a patient cohort from 13 disease sites containing at least 100 patients in each disease site. With a minimum of 12 years of follow-up, current smoking increased OM risk versus recent quit (HR 1.17), former (HR 1.29) and never smokers (HR 1.38) in the overall cohort. Current smoking increased DSM risk versus former (HR 1.23) and never smokers (HR 1.18). In disease sites with proportionately large (>20%) recent quit cohorts (lung and head/neck), current smoking increased OM and DSM risks as compared with recent quit. Current smoking increased mortality risks in lung, head/neck, prostate and leukemia in men and breast, ovary, uterus and melanoma in women. Current smoking was not associated with any survival benefit in any disease site. Data using prospective structured smoking assessments demonstrate that current smoking increased long-term OM and DSM. Standardized smoking assessment at diagnosis is an important variable for evaluating outcomes in cancer patients.

Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can)

We investigated associations between metabolic factors and blood cancer subtypes. Data on body mass index (BMI), blood pressure, blood glucose, total cholesterol, and triglycerides from seven prospective cohorts were pooled (n = 578,700; mean age = 44 years). Relative risks of blood cancers were calculated from Cox regression models. During mean follow-up of 12 years, 2,751 incident and 1,070 fatal cases of blood cancers occurred. Overall, higher BMI was associated with an increased blood cancer risk. In gender-specific subgroup analyses, BMI was positively associated with blood cancer risk (p = 0.002), lymphoid neoplasms (p = 0.01), and Hodgkin's lymphoma (p = 0.02) in women. Further associations with BMI were found for high-grade B-cell lymphoma (p = 0.02) and chronic lymphatic leukemia in men (p = 0.05) and women (p = 0.01). Higher cholesterol levels were inversely associated with myeloid neoplasms in women (p = 0.01), particularly acute myeloid leukemia (p = 0.003), and glucose was positively associated with chronic myeloid leukemia in women (p = 0.03). In men, glucose was positively associated with risk of high-grade B-cell lymphoma and multiple myeloma, while cholesterol was inversely associated with low-grade B-cell lymphoma. The metabolic syndrome score was related to 48 % increased risk of Hodgkin's lymphoma among women. BMI showed up as the most consistent risk factor, particularly in women. A clear pattern was not found for other metabolic factors.

Exposure to Benzene and Risk of Breast Cancer among Shoe Factory Workers in Italy

Evidence of the association between leukemia and benzene exposure has been provided by several epidemiological studies. An increased risk of breast cancer among women exposed to benzene has also been suggested. The aim of this study was to analyze breast cancer risk in a cohort of 1,002 women exposed to benzene in a shoe factory in Florence, Italy, where an excess of leukemia in men was reported. The cohort of women at work on January 1st, 1950, was followed from 1950 to 2003 for mortality and from 1985 to 2000 for incidence of breast cancer. For a sub-cohort of 797 women, cumulative exposure to benzene was available. Standardized mortality ratios were obtained for the 797 women for whom information on cumulative exposure was available. For those with < 30 years of latency the standardized mortality ratio was 58.5 (95% CI, 18.9-181.2, based on 3 deaths) and 151.1 (95% CI, 78.6-290.3, based on 9 deaths) for > or = 30 years of latency. In the > 40 ppm-year and > or = 30 year latency period category, the standardized mortality ratio was 166.0 (95% CI, 62.3-442.2, based on 4 deaths). The standardized incidence ratio for women with a latency period < 30 years was 140.9 (95% CI, 75.8-261.9, based on 10 cases) and 108.2 (95% CI, 64.1-182.7) for a latency period > or = 30 years. For cumulative exposure > 40 ppm-years and a latency period < 30 years, the standardized incidence ratio was 211.9 (95% CI, 29.9-1504.1, based on 1 case). The study moderately supports the hypothesis that benzene represents a risk factor for breast cancer.

Characterization of C-, J- and V-region-genes of the feline T-cell receptor γ

Lymphomas and leukemias are important neoplasias of domestic cats and human beings. In some cases it can be difficult to differentiate these tumors from reactive lymphatic hyperplasia. To overcome this problem, the diagnosis of lymphomas and leukemias in man is often supported by molecular techniques. To be able to establish such a technique in the cat we had to sequence the genes coding for the antigen receptors. As primary target in this study we choose the T-cell receptor γ. Using 5′-and 3′-RACE techniques we were able to clone and sequence four different V-region genes, which can be clustered into two subgroups as well as six variants of the C-region gene. Additionally, we found eight J-region genes which can be classified into three subgroups. One of the V-region genes, six of the J-region genes and all C-region genes had not been described previously. All together we analysed 112 clones containing V- and J-region genes and 31 clones containing C-region genes. Sixty-six of these clones were full length containing the L-region as well as the 5′-UTR of the feline T-cell receptor γ. The sequences of the V-region- and J-region-genes show sufficiently homologous areas that can be used to establish a small number of consensus-primers to be applied in molecular diagnosis of feline lymphomas and leukemias.

Long‐term experience with imatinib therapy in chronic phase chronic myelogenous leukemia—Remarkable activity with room for improvement

Long‐term experience with imatinib therapy in chronic phase chronic myelogenous leukemia—Remarkable activity with room for improvement

Cancer risk analysis of low-dose radiation exposure

Cancer risk assessment was conducted in a population that received prolonged low dose-rate γ-irradiation for about 10 years as a result of occupying buildings containing 60Co-contaminated steel in Taiwan. The cancer risks were compared with those populations with the same temporal and geographic characteristics in Taiwan by standardized incidence ratios, adjusted for age and gender. The standardized incidence ratios were significantly higher for all leukemia except chronic lymphocytic leukemia in men, and marginally significant for thyroid cancers in women. All cancers combined were shown to exhibit significant exposure-dependent increased risks in individuals with the initial exposure before 30 years of age, but not beyond this age. Excess relative risk at 1 Sv by Cox proportional hazard model was significantly high in all cancers combined, breast cancers and leukemia, while it was marginally significant in solid cancers combined, all solid cancers combined, stomach cancers and lung cancers. The results indicated that protracted low-dose radiation could induce higher cancer risks in the general public, especially for leukemia and the risks were comparable with those of acute radiation exposure.

Aplicação de uma metodologia de screening para avaliar a mortalidade por câncer em municípios selecionados do Estado de Minas Gerais, Brasil

An epidemiological investigation was launched in several cities in southern Minas Gerais State, Brazil, considering the possibility of increased cancer incidence due to high exposure to natural radiation. First, the cancer mortality patterns were assessed to determine whether there was an increase in cancer deaths and to discuss the possible risk factors related to such an increase. The study proposed the use of a screening methodology based on standardized mortality ratio (SMR) in order to classify priority areas for future studies. Cities considered high priority for further investigation were: Andradas, for lung cancer in men (SMR = 208 (106-310)) and liver cancer in women (SMR = 403 (104-701)); Poços de Caldas, leukemia in men and women (SMR = 284 (156-412)) and SMR = 211 (111-312), respectively); Pouso Alegre, leukemia in men (SMR = 333 (127-540)) and hematological cancers in women (SMR = 257 (188-396)). Epidemiological studies are necessary to evaluate the role of radiation and other risk factors in these cancers and thus to support future preventive and control measures.

Polymorphism of the human HA-RAS oncogene locus in chronic lymphocytic and chronic myelogenous leukemia

DNA from white blood cells from healthy controls demonstrates a restriction fragment length polymorphism (RFLP) of the Ha-ras oncogene locus after cleavage with the restriction enzymes BamH I or MspI plus HpaII, representing frequent and rare alleles. We have studied the RFLP of 15 patients with B-cell chronic lymphocytic (CLL) and of 16 patients with chronic myelogenous leukemia (CML). As in healthy controls the RFLP in the leukemic cells indicates the occurrence of frequent and rare Ha-ras alleles. But rare alleles are not more frequent in the patients than in the healthy control group. The frequency of rare Ha-ras alleles also does not differ between chronic lymphocytic and chronic myelogenous leukemia. While rare alleles of this oncogene locus occur in CML and CLL as frequently as in healthy controls, they do not reflect an inherent increased risk for chronic leukemia in man.

The Icsbp locus is a common proviral insertion site in mature B-cell lymphomas/plasmacytomas induced by exogenous murine leukemia virus

ICSBP (interferon consensus sequence binding protein)/IRF8 (interferon regulatory factor 8) is an interferon gamma-inducible transcription factor expressed predominantly in hematopoietic cells, and down-regulation of this factor has been observed in chronic myelogenous leukemia and acute myeloid leukemia in man. By screening about 1200 murine leukemia virus (MLV)-induced lymphomas, we found proviral insertions at the Icsbp locus in 14 tumors, 13 of which were mature B-cell lymphomas or plasmacytomas. Only one was a T-cell lymphoma, although such tumors constituted about half of the samples screened. This indicates that the Icsbp locus can play a specific role in the development of mature B-lineage malignancies. Two proviral insertions in the last Icsbp exon were found to act by a poly(A)-insertion mechanism. The remaining insertions were found within or outside Icsbp. Since our results showed expression of Icsbp RNA and protein in all end-stage tumor samples, a simple tumor suppressor function of ICSBP is not likely. Interestingly, proviral insertions at Icsbp have not been reported from previous extensive screenings of mature B-cell lymphomas induced by endogenous MLVs. We propose that ICSBP might be involved in an early modulation of an immune response to exogenous MLVs that might also play a role in proliferation of the mature B-cell lymphomas.