CDK4/6 inhibitors are considered a breakthrough in cancer therapy. Currently approved for breast cancer treatment, CDK4/6 inhibitors are extensively tested in other cancer subtypes. Frequently observed side effects include hematological abnormalities such as reduced numbers of neutrophils, erythroid cells and platelets that are associated with anemia, bleedings and a higher risk of infections. To understand whether the adverse effects within the hematopoietic system are related to CDK4 or CDK6 we generated transgenic mice that lack either CDK4 or CDK6 in adult hematopoiesis. Anemia and perturbed erythroid differentiation are associated with the absence of CDK6 but did not manifest in CDK4-deficient mice. Total CDK6 knockout mice accumulate the most dormant fraction of hematopoietic stem cells due to an impaired exit of the quiescent state. We recapitulated this finding by deleting CDK6 in adult hematopoiesis. In addition, unlike total CDK6 knockout, all stem cell fractions were affected and increased in numbers. The deletion of CDK6 was also accompanied by neutropenia which is frequently seen in patients receiving CDK4/6 inhibitors. This was not the case in the absence of CDK4; CDK4 deficiency resulted in elevated numbers of myeloid progenitors without translating into numeric changes of differentiated myeloid cells. By using Cdk4fl/fl and Cdk6fl/fl mice we assign side effects of CDK4/6 inhibitors predominantly to the absence of CDK6. These mice represent a novel and powerful tool that will enable to study the distinct functions of CDK4 and CDK6 in a tissue-dependent manner.While ineffective erythropoiesis has long been recognized as a key contributor to anemia in thalassemia, its role in anemia of sickle cell disease (SCD) has not been critically explored. selleck kinase inhibitor Using in vitro and in vivo derived human erythroblasts we assessed the extent of ineffective erythropoiesis in SCD. Modeling the bone marrow hypoxic environment, we found that hypoxia induces death of sickle erythroblasts starting at the polychromatic stage, positively selecting cells with high levels of fetal hemoglobin (HbF). Cell death was associated with cytoplasmic sequestration of heat shock protein 70 and was rescued by induction of HbF synthesis. Importantly, we document that in bone marrow of SCD patients similar cell loss occurs during the final stages of terminal differentiation. Our study provides evidence for ineffective erythropoiesis in SCD and highlights an anti-apoptotic role for HbF during the terminal stages of erythroid differentiation. These findings imply that the beneficial effect on anemia of increased HbF levels is not only due to the increased life span of red cells but also a consequence of decreased ineffective erythropoiesis.In situ follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified 10 paired cases of ISFN and DLBCL/HGBL, including 6 de novo tumors and 4 transformed from FL as intermediate step, and investigated their clonal evolution using microdissection and next generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations for all 10 cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as intermediate step and that during this progression, branched evolution is common.Vaso-occlusive crises are the hallmark of sickle cell disease (SCD). They are believed to occur in two steps, starting with adhesion of deformable low-dense red blood cells (RBCs), or other blood cells such as neutrophils, to the wall of post-capillary venules, followed by trapping of the denser RBCs or leukocytes in the areas of adhesion because of reduced effective lumen-diameter. In SCD, RBCs are heterogeneous in terms of density, shape, deformability and surface proteins, which accounts for the differences observed in their adhesion and resistance to shear stress. Sickle RBCs exhibit abnormal adhesion to laminin mediated by Lu/BCAM protein at their surface. This adhesion is triggered by Lu/BCAM phosphorylation in reticulocytes but such phosphorylation does not occur in mature dense RBCs despite firm adhesion to laminin. In this study, we investigated the adhesive properties of sickle RBC subpopulations and addressed the molecular mechanism responsible for the increased adhesion of dense RBCs to laminin in the absence of Lu/BCAM phosphorylation. We provide evidence for the implication of oxidative stress in post-translational modifications of Lu/BCAM that impact its distribution and cis-interaction with glycophorin C at the cell surface activating its adhesive function in sickle dense RBCs.Combination treatment has proven effective for patients with acute promyelocytic leukemia, exemplifying the importance of therapy targeting multiple components of oncogenic regulation for a successful outcome. However, recent studies have shown that the mutational complexity of acute myeloid leukemia (AML) precludes the translation of molecular targeting into clinical success. Here as a complement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop personalized combinatorial treatments. First, we screened 513 natural compounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AMLs, while FLT3-ITD/mutations conferred resistance. The responding samples to H4, displayed increased expression of myeloid markers, a clear decrease in the nuclear-cytoplasmic ratio and the potential of re-activation of the monocytic transcriptional program reducing leukemia propagation in vivo.