Adult Hepatocellular Carcinoma Coexisting with Extramedullary Hematopoiesis

Extramedullary hematopoiesis (EMH) in adults usually occurs in the liver, spleen, and lymph nodes when bone marrow hematopoiesis fails. EMH has also been recognized in benign or malignant hepatic tumors, such as hepatoblastoma, hepatocellular adenoma, and vascular tumors. However, it is rarely encountered in hepatocellular carcinoma (HCC) in elderly adults, and the molecular mechanism of EMH in hepatic tumors remains unclear. We present a case of a 74-year-old man without any hematopoietic disorders and hepatitis viral infection who underwent hepatic resection for HCC. Histological examination revealed a well-differentiated HCC with trilineage hematopoiesis in the tumor and non-neoplastic liver. The coexistence of HCC and EMH in adult patients with no hematopoietic disorders is very rare and must be distinguished from poorly differentiated or dedifferentiated HCC and hepatoblastoma.

Towards Understanding the Pathogenicity of DROSHA Mutations in Oncohematology

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders, which are characterized by accumulation of somatic mutations. The acquired mutation burden is suggested to define the pathway and consequent phenotype of the pathology. Recent studies have called attention to the role of miRNA biogenesis genes in MDS progression; in particular, the mutational pressure of the DROSHA gene was determined. Therefore, this highlights the importance of studying the impact of all collected missense mutations found within the DROSHA gene in oncohematology that might affect the functionality of the protein. In this study, the selected mutations were extensively examined by computational screening, and the most deleterious were subjected to a further molecular dynamic simulation in order to uncover the molecular mechanism of the structural damage to the protein altering its biological function. The most significant effect was found for variants I625K, L1047S, and H1170D, presumably affecting the endonuclease activity of DROSHA. Such alterations arisen during MDS progression should be taken into consideration as evoking certain clinical traits in the malignifying clonal evolution.

Hepatobiliary and Gastrointestinal Involvement in Langerhans Cell Histiocytosis—Spectrum of Three Cases

Langerhans cell histiocytosis (LCH) is a rare group of disorder, due to clonal neoplastic proliferation of dendritic cells in the bone marrow expressing a Langerhans cell phenotype.1 This disease particularly affects the pediatric age group and young adults and often presents with skin rashes, lung infiltrates, and bone lesions. It can also manifest with endocrine dysfunction and hematopoietic disorders. Involvement of gastrointestinal tract is very rare. Herein, we present a spectrum of three cases with gastrointestinal involvement.

Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients

Unrelated cord blood transplantation (UCBT) is an effective treatment for hematopoietic disorders. However, this attractive approach is frequently accompanied by pre-engraftment syndrome (PES), severe cases of PES are associated with enhanced mortality and morbidity, but the pathogenesis of PES remains unclear. Here we show that GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and that monocytes are the main source of IL-6 during PES. Further, we report the outcome of a single arm, single-center clinical study of tocilizumab in the treatment of steroid-refractory severe PES patients (www.chictr.org.cn ChiCTR1800015472). The study met the primary outcome measure since none of the patients was nonrelapse death during the 100 days follow-up. The study also met key secondary outcomes measures of neutrophil engraftment and hematopoiesis. These findings offer a therapeutic strategy with which to tackle PES and improve nonrelapse mortality.

Novel Therapies in Myeloproliferative Neoplasms: Beyond JAK Inhibitor Monotherapy

ABSTRACT Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that consist classically of polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Janus kinase (JAK) inhibitors have become the standard of therapy in treating patients with intermediate- to higher-risk MF. However, JAK inhibitor (JAKi) treatment can be associated with development of resistance, suboptimal response, relapse, or treatment-related adverse effects. With no approved therapies beyond the JAKi class, the estimated median survival, post JAKi failure, is approximately two years or less; therefore, novel therapies are urgently needed in the MF field. In this review, we discuss ruxolitinib use in MPNs as well as causes of ruxolitinib failure or discontinuation. In addition, we review novel therapies being investigated alone or in combination with JAKi administration. We summarize concepts and mechanisms behind emerging novel therapies being studied for MPNs. This review of emerging novel therapies outlines several novel mechanisms of agents, including via promotion of apoptosis, alteration of the microenvironment, activation or inactivation of various pathways, targeting fibrosis, and telomerase inhibition.

Novel combined variants of WT1 and TET2 in a refractory and recurrent AML patient

Background Somatic mutations in Wilms' tumor 1 (WT1) and tet methylcytosine dioxygenase 2 (TET2) genes were separately perceived as contributors to hematopoietic disorders and usually thought to have a mutually exclusive effect in acute myeloid leukemia (AML). However, we found novel WT1 and TET2 variants persistently co-existed in a refractory and recurrent AML patient with t(9;11)(p21.3;q23.3); KMT2A-MLLT3, and were only detectable genetic alteration in early recurrence. Hence, these two novel variants were further investigated in patient’s family, and the potential effect on disease progression was evaluated at follow-up. Case presentation A 27-year-old male was diagnosed with AML, having t(9;11)(p21.3;q23.3); KMT2A-MLLT3, accompanied by WT1 (NM_024426.6:exon7:c.1109G>C:p.Arg370Pro) and TET2 (NM_001127208.3:exon11:c.5530G>A:p.Asp1844Asn) variants. After two cycles of induction chemotherapy, complete remission was achieved. A consolidation treatment was then completed. However, the evaluation of the bone marrow revealed that early recurrence, WT1 (p.Arg370Pro) and TET2 (p.Asp1844Asn) variants still detectable, instead of KMT2A-MLLT3. Subsequently, these two variants were proved to be germline variants, which inherited from father and mother respectively. And the patient's elder brother also carried TET2 (p.Asp1844Asn) variant. A sequential allogeneic HLA-matched sible hematopoietic stem cell transplantation (allo-HSCT) was carried out, and the donor is the patient's elder brother, the original two variants of patient were replaced by the donor-derived TET2 (p.Asp1844Asn) variant after allo-HSCT; the patient has remained in complete remission with regular follow-up. Conclusions In brief, it is firstly reported that WT1 p.Arg370Pro and TET2 p.Asp1844Asn variants co-existed in a refractory and recurrent AML patient by inheritance. These two variants of the patient were replaced with donor-derived TET2 p.Asp1844Asn after allo-HSCT, and the patient has remained in complete remission with regular follow-up.

Receptor-mediated mitophagy regulates EPO production and protects against renal anemia

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

son is necessary for proper vertebrate blood development

The gene SON is on human chromosome 21 (21q22.11) and is thought to be associated with hematopoietic disorders that accompany Down syndrome. Additionally, SON is an RNA splicing factor that plays a role in the transcription of leukemia-associated genes. Previously, we showed that mutations in SON cause malformations in human and zebrafish spines and brains during early embryonic development. To examine the role of SON in normal hematopoiesis, we reduced expression of the zebrafish homolog of SON in zebrafish at the single-cell developmental stage with specific morpholinos. In addition to the brain and spinal malformations we also observed abnormal blood cell levels upon son knockdown. We then investigated how blood production was altered when levels of son were reduced. Decreased levels of son resulted in lower amounts of red blood cells when visualized with lcr:GFP transgenic fish. There were also reduced thrombocytes seen with cd41:GFP fish, and myeloid cells when mpx:GFP fish were examined. We also observed a significant decrease in the quantity of T cells, visualized with lck:GFP fish. However, when we examined their hematopoietic stem and progenitor cells (HSPCs), we saw no difference in colony-forming capability. These studies indicate that son is essential for the proper differentiation of the innate and adaptive immune system, and further investigation determining the molecular pathways involved during blood development should elucidate important information about vertebrate HSPC generation, proliferation, and differentiation.