A better understanding of how signaling pathways govern cell fate is fundamental to advances in cancer development and treatment. The initialization of different tumors and their maintenance are caused by the deregulation of different signaling pathways and cancer stem cell maintenance. Quiescent stem cells are resistant to conventional chemotherapeutic treatments and, consequently, are responsible for disease relapse. In this review we focus on the conserved Hedgehog (Hh) signaling pathway which is involved in regulating the cell cycle of hematopoietic and leukemic stem cells. Thus, we examine the role of the Hh signaling pathway in normal and leukemic stem cells and dissect its role in acute myeloid leukemia. We explain not only the connection between illness and the signaling pathway but also evaluate innovative therapeutic approaches that could affect the outcome of patients with acute myeloid leukemia. We found that many aspects of the Hedgehog signaling pathway remain unknown. The role of Hh has only been proven in embryo and hematopoietic stem cell development. Further research is needed to elucidate the role of GLI transcription factors for therapeutic targeting. Glasdegib, an SMO inhibitor, has shown clinical activity in acute myeloid leukemia; however, its mechanism of action is not clear.

The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs.

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.

Summary: Until now, the role that seasonal factors play in the aetiology of acute myeloid leukaemia (AML) has been unclear. Demonstration of seasonality in AML diagnosis would provide supportive evidence of an underlying seasonal aetiology. To investigate the potential seasonal and long‐term trends in AML diagnosis in an overall population and in subgroups according to sex and age, we used population‐based data from a Spanish hospital discharge registry. We conducted a larger study than any to date of 26 472 cases of AML diagnosed in Spain between 2004 and 2015. Using multivariable Poisson generalized linear autoregressive moving average modelling, we found an upward long‐term trend, with monthly incidence rates of AML annually increasing by 0.4% [95% confidence interval (CI), 0.2%–0.6%; p = 0.0011]. January displayed the highest incidence rate of AML, with a minimum average difference of 7% when compared to February (95% CI, 2%–12%; p = 0.0143) and a maximum average difference of 16% compared to November (95% CI, 11%–21%; p < 0.0001) and August (95% CI, 10%–21%; p < 0.0001). Such seasonal effect was consistent among subgroups according to sex and age. Our finding that AML diagnosis is seasonal strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development and/or proliferation of disease, pointing to prevention opportunities.

We retrospectively evaluated 2879 hospitalized COVID-19 patients from four hospitals to evaluate the ability of demographic data, medical history, and on-admission laboratory parameters to predict in-hospital mortality. Association of previously published risk factors (age, gender, arterial hypertension, diabetes mellitus, smoking habit, obesity, renal failure, cardiovascular/ pulmonary diseases, serum ferritin, lymphocyte count, APTT, PT, fibrinogen, D-dimer, and platelet count) with death was tested by a multivariate logistic regression, and a predictive model was created, with further validation in an independent sample. A total of 2070 hospitalized COVID-19 patients were finally included in the multivariable analysis. Age 61–70 years (p<0.001; OR: 7.69; 95%CI: 2.93 to 20.14), age 71–80 years (p80 years (p<0.001; OR: 36.78; 95%CI: 14.42 to 93.85), male gender (p2 ULN (p= 0.003; OR: 1.79; 95%CI: 1.22 to 2.62), and prolonged PT (p<0.001; OR: 2.18; 95%CI: 1.49 to 3.18) were independently associated with increased in-hospital mortality. A predictive model performed with these parameters showed an AUC of 0.81 in the development cohort (n = 1270) [sensitivity of 95.83%, specificity of 41.46%, negative predictive value of 98.01%, and positive predictive value of 24.85%]. These results were then validated in an independent data sample (n = 800). Our predictive model of in-hospital mortality of COVID-19 patients has been developed, calibrated and validated. The model (MRS-COVID) included age, male gender, and on-admission coagulopathy markers as positively correlated factors with fatal outcome.