Malignant Blood Research Articles

Clinical analysis of 11 cases of nocardiosis.

Nocardiosis is a rare, life-threatening, opportunistic, and suppurative infection. Its clinical manifestation lacks specificity, which makes early diagnosis difficult. A retrospective analysis of the clinical records of 11 patients with nocardiosis admitted to our hospital from January 2013 to November 2018 was conducted. All patients had at least one underlying disorder, such as an autoimmune disease (6/11), a blood malignancy (2/11), avascular necrosis of the femoral head (1/11), bronchiectasis (1/11), or pneumonia (1/11). The first-line treatment was trimethoprim–sulfamethoxazole (TMP–SMX); one or two additional antibiotics were given according to the drug-sensitive test. The median time from onset to treatment was 3 weeks (ranging from 1 to 9 weeks). The median duration of treatment after diagnosis was 20.5 weeks (ranging from 7 to 47 weeks). Eight patients were discharged and survived, and three patients died. This indicates that early use of TMP–SMX combined with sensitive antibiotics could improve the condition of patients and improve the cure rate (8/11). Clinically, it is necessary to consider the possibility of nocardiosis in patients with long-term use of immunosuppressants and poor response to treatment of common bacterial infections. Early diagnosis, timely treatment, and combination drug therapy are keys to improving the outcomes of patients with nocardiosis.

The Enigmatic Emerging Role of the C-Maf Inducing Protein in Cancer.

The C-Maf-Inducing protein (CMIP) was first described as overexpressed in T cell subpopulations of idiopathic nephrotic syndrome (INS) patients. Later, it was found concomitantly upregulated in podocytes. CMIP expression has also been reported in several types of cancer, including blood malignancies and solid tumors, in many cases accompanied by nephrotic syndrome. In addition to these observations, the duality of CMIP overexpression in the kidney and INS lesions, has been extensively reported as one of the adverse effects of anticancer therapy based on anti-receptor tyrosine kinase drugs. As a consequence, a growing body of evidence points at CMIP as playing a role in cancer. This includes its reciprocal regulatory ties with NF-κB and WT1, and the more recent reports showing an involvement in regulatory circuits in cancer cells. The ensemble of the current information justifies to propose CMIP as an important piece of the puzzle of biological systems involved in cancer and other diseases and its potential as a target.

Epigenetic‐based therapy in allogenic hematopoietic stem cell transplantation: Novel opportunities for personalized treatment

Current management of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) lacks immunosuppressant drugs able to block the host immune response toward the graft antigens. Novel treatments may include epigenetic compounds (epidrugs) some of which have been yet approved by the Food and Drugs Administration for the treatment of specific blood malignancies. The most investigated in clinical trials for allo-HSCT are DNA demethylating agents (DNMTi), such as azacitidine (Vidaza) and decitabine (Dacogen) as well as histone deacetylases inhibitors (HDACi), such as vorinostat (Zolinza) and panobinostat (Farydak). Indeed, azacitidine monotherapy before allo-HSCT may reduce the conventional chemotherapy-related complications, whereas it may reduce relapse risk and death after allo-HSCT. Besides, a decitabine-containing conditioning regimen could protect against graft versus host disease (GVHD) and respiratory infections after allo-HSCT. Regarding HDACi, the addition of vorinostat and panobinostat to the conditioning regimen after allo-HSCT seems to reduce the incidence of acute GVHD. Furthermore, panobinostat alone or in combination with low-dose decitabine may reduce the relapse rate in high-risk patients with acute myeloid leukemia patients after allo-HSCT. We discuss the phase 1 and 2 clinical trials evaluating the possible beneficial effects of repurposing specific epidrugs which may guide personalized therapy in the setting of allo-HSCT.

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism.

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.

An aging mouse model of human chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival. This model was developed by noncytotoxic depletion of bone marrow lineage-positive cells followed by BCR-ABL retroviral transduction and transplantation. CML developed in aging mice shared many similarities to that in young mice, but had increased incidence of anemia that is often seen in human CML. Importantly, we showed that aging of both donor hematopoietic stem cells and recipient bone marrow niche impacted BCR-ABL mediated leukemogenesis and leukemia spectrum. Optimal CML induction relied on age-matching for donors and recipients, and cross-transplantation between young and old mice produced a mixture of different leukemia. Therefore, our model provides initial evidence of the feasibility and merit of CML modeling in aging mice and offers a new tool for future studies of CML stem cell drug resistance and therapeutic intervention in which aging would be taken into consideration as an influencing factor.

Difficulties in diagnosing multiple myeloma with lung damage

Multiple myeloma occupies a leading position among malignant blood diseases. There is clinical evidence that multiple myeloma can be complicated by secondary amyloidosis. The article presents a clinical case for the diagnosis of multiple myeloma complicated by secondary pulmonary amyloidosis. The participation of doctors of various specialties (pulmonologist, hematologist, pathologist), the use of high-tech diagnostic methods (histological examination of a biopsy of lung tissue, trepanobiopsy, immunohistochemical examination of histological preparations of lungs and bone marrow), made it possible to establish a clinical diagnosis.

Secretion of bispecific protein of anti-PD-1 fused with TGF-β trap enhances antitumor efficacy of CAR-T cell therapy

Despite the remarkable success of chimeric antigen receptor-modified T (CAR-T) cell therapy for blood malignancies, the clinical efficacy of this novel therapy in solid tumor treatment is largely limited by the immunosuppressive tumor microenvironment (TME). For instance, immune checkpoints (e.g., programmed cell death protein 1 [PD-1]/programmed death ligand 1 [PD-L1]) in TME play an important role in inhibiting T cell proliferation and functions. Transforming growth factor β (TGF)-β secreted by cancer cells in TME induces regulatory T cells (Tregs) and inhibits cytotoxic T cells. To overcome the inhibitory effect of immune checkpoints, we have previously engineered CAR-T cells to secrete anti-PD-1 to block the PD-1/PD-L1 pathway activity, a step demonstrating superior antitumor efficacy compared with conventional CAR-T cells. In this study, we engineered CAR-T cells that secrete bispecific trap protein co-targeting PD-1 and TGF-β, with the aim of further improving antitumor immunity. Compared with conventional CAR-T cells and anti-PD-1-secreting CAR-T cells, data from in vitro and in vivo experiments showed that CAR-T cells with trap protein secretion further attenuated inhibitory T cell signaling, enhanced T cell persistence and expansion, and improved effector function and resistance to exhaustion. In the xenograft mouse model, CAR-T cells with trap protein secretion exhibited significantly enhanced antitumor immunity and efficacy. With these observations, we demonstrate the potential of trap protein self-secreting CAR-T cells as a potent therapy for solid tumors.

POS-190 RENAL PROGNOSIS OF HEMOLYTIC UREMIC SYNDROME IN ADULTS

Hemolytic uremic syndrome (HUS) is caused by intrarenal thrombotic microangiopathy, leading to high blood pressure and acute renal failure. The most common form of HUS is secondary to shiga toxin-producing bacteria, typically Escherichia coli. Atypical HUS (aHUS) has been used to classify any HUS not caused by shiga toxin. It is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The aim of our study was to determinate the clinical features and the renal prognosis of the HUS occurring in adults. We conducted a retrospective study of 19 patients over a period of 27 years (1990-2017) in our nephrology department. We defined hypertension as an increase in systolic blood pressure > 140 mmhgand / or diastolic blood pressure > 90 mmhg on the basis of the Europeandefe society of cardiology We defined anemia as a hemoglobin levels lower than 13 g/100ml for adult males, 12 g/100ml for adult females non pregnant, 11 g/100ml for adult females pregnant. We defined thrombocytopenia as platelets levels lower than 150000/mm3. AKI is defined as any of the following (Not Graded): Increase in SCr by X0.3 mg/dl (X26.5 lmol/l) within 48 hours or Increase in SCr to X1.5 times baseline, which is known or presumed to have occurred within the prior 7 days or Urine volume o0.5 ml/kg/h for 6 hours on the basis of KDIGO. We included patients aged over 16 years old with biopsy proven thrombotic microangiopathy. We collected the following parameters: age, gender, co morbidities, clinical exam, biological assessment, treatment We included 19 patients. There were 15 men (79%) and 4 women (21%), sex ratio 3,75 with a median age 36 years old (19- 60). The inaugural symptoms were dominated by headaches in 52% of cases. It was associated to malignant high blood pressure. The median of PAS was 178mmHg. And the median of PAS was 120 mmHg, the median of PAM was 143 mmHg. The median creatinine at diagnosis was 786 μmol /l (350 – 1940μmol /l). The blood smear revealed schizocytes in 11 cases (58%). The median hemoglobin was 6,3 g/dl (4,5 – 7,8g/dl). The haptoglobin level in 7 patients was low in 3 cases. The median platelets was 110000 /mm3 (45000 – 143000). The serum complement C3 was consumed in 64% of cases. A glomerular thrombotic microangiopathy was objectified in 42% of cases. For the etiologies, the HUS was related to gene mutations, pregnancy, infections, cancer in respectively 21%, 5%, 10% and 5% of cases. For the other cases the cause remains unknown. The treatment combined corticosteroid therapy (1mg/Kg/j) in all cases with plasma exchanges in 26% of cases. The evolution has been marked by a progressive improvement in renal function in 37% of cases but 74% of patients maintained chronic kidney failure then requiring hemodialysis in 58% of cases after a mean of follow-up of 14 months (3 to 32 months) Three patients had kidney transplant. One death occurred and was secondary to acute pulmonary edema. The diagnosis of aHUS is complex and challenging, but is essential because of the devastating consequences of inadequate treatment. The prognosis of HUS has been improved by plasma exchange but chronic renal insufficiency is still common.

Common Concerns of Cancer Patients in the Time of COVID-19 Outbreak: Some Implications for Health Care Professionals

Coronaviruses are important human and animal pathogens. In December 2019, a new virus from the coronavirus family, called coronavirus disease 2019 (COVID-19), triggered the outbreak of pneumonia from Wuhan across China. The virus originated in bats and was transmitted to humans through unknown intermediate animals. Currently, the lives of millions of people around the world are affected by the crisis caused by the outbreak of COVID-19 diseases, which has brought huge economic and social costs. Despite the efforts made in many countries to reduce the risks and the negative effects of this crisis, the damage and the resulting costs are still increasing. People with cancer are among the groups that need more attention and are highlighted as high-risk groups. The risk of morbidity and mortality from COVID-19 as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not uniform. Evidence show that patients with cancer have an increased risk of developing severe forms of COVID-19 compared with the non-cancer population. It seems that cancer patients are at a higher risk of respiratory viruses such as influenza because of their frequently observed immunocompromised state. Patients with blood malignancies, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma, along with those in active treatment for any type of cancer and people who have undergone bone marrow transplants are among the high-risk groups.

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments.

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

Immunoprofiling of Drosophila Hemocytes by Single-cell Mass Cytometry

Single-cell mass cytometry (SCMC) combines features of traditional flow cytometry (i.e., fluorescence-activated cell sorting) with mass spectrometry, making it possible to measure several parameters at the single-cell level for a complex analysis of biological regulatory mechanisms. In this study, weoptimizedSCMC to analyze hemocytes of the Drosophila innate immune system. We used metal-conjugated antibodies (against cell surface antigens H2, H3, H18, L1, L4, and P1, and intracellular antigens 3A5 and L2) and anti-IgM (against cell surface antigen L6) to detect the levels of antigens, while anti-GFP was used to detect crystal cells in the immune-induced samples. We investigated the antigen expression profile of single cells and hemocyte populations in naive states, in immune-induced states, in tumorous mutants bearing a driver mutation in the Drosophila homologue of Janus kinase (hopTum) and carrying a deficiency of the tumor suppressor gene lethal(3)malignant blood neoplasm-1 [l(3)mbn1], as well as in stem cell maintenance-defective hdcΔ84 mutant larvae. Multidimensional analysis enabled the discrimination of the functionally different major hemocyte subsets for lamellocytes, plasmatocytes, and crystal cells, anddelineated the unique immunophenotype of Drosophila mutants. We have identified subpopulations of L2+/P1+ and L2+/L4+/P1+ transitional phenotype cells in the tumorous strains l(3)mbn1 and hopTum, respectively, and a subpopulation of L4+/P1+ cells upon immune induction. Our results demonstrated for the first time that SCMC, combined with multidimensional bioinformatic analysis, represents a versatile and powerful tool to deeply analyze the regulation of cell-mediated immunity of Drosophila.

PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role.

Hematopoietic cancers are among the most common malignancies worldwide, which are divided into different types depending on the origin of tumor cells. In recent years, the pivotal role of different signaling pathways in the onset and progression of these cancer types has been well established. One of these pathways, whose role in blood malignancies has been well‐defined, is PI3K/mTOR/AKT axis. The signaling pathway involves in a wide variety of important biological events in cells. It is clear that dysregulation of mediators involved in PI3 kinase signaling takes a pivotal role in cancer development. Considering the undeniable role of miRNAs, as one of the well‐known families of non‐coding RNAs, in gene regulation, we aimed to review the role of miRNAs in regulation of PI3 kinase signaling effectors in hematopoietic cancers.

Abstract PO007: Role of PI3K pathway in reprogramming the tumor niche of angiosarcoma

Abstract Angiosarcoma (AS) is a highly aggressive, rare soft-tissue sarcoma that forms malignant blood vessels. Approximately half of patients have metastatic or unresectable disease with a median overall survival of less than 6 months, and tumor-related mortality is high. Inflamed tissue is frequently seen in angiosarcomas, and immune cells are key components that contribute to the landscape of the tumor microenvironment. Hemangiosarcoma (HSA) occurs commonly in companion dogs, and it shares clinical and morphological features with human AS. Recurrent mutations in TP53 and genes involved in PI3K pathway such as PIK3CA, and PIK3R1 were observed in both human AS and canine HSA, and the mutational landscape was associated with distinct molecular tumor subtypes; in particular, differing immunophenotypes. Recently, we have shown that human AS and canine HSA establish convergent transcriptional programs driven by angiogenic fusion genes and TP53 mutation. However, these vascular tumors are genomically complex, and molecular mechanisms that establish the tumor microenvironment are incompletely known. In this study, we analyzed RNA-seq transcriptomic data generated from human AS tissues (n=13) and canine HSA tissues (n=76) and HSA cell lines (n=11). The data showed that the tumors of both species enriched gene signatures associated with maintenance of hematopoietic stem cells. Then, we found that canine HSA cells supported expansion and differentiation of human CD34+ umbilical cord blood cells using long-term culture-initiating cell and colony-forming unit assays. We also developed xenograft models of canine HSA that facilitate myelopoiesis and macrophage infiltration in the tumor tissue. Our data showed that gene signatures of monocytes and naïve macrophages were detectable in canine HSA cells. In human ASs, macrophage-associated genes, in particular M2 macrophage signatures were significantly enriched, compared to normal tissues. Collectively, our data suggest that human AS and canine HSA have cell-autonomous capacity to govern hematopoietic progenitors and immune cells, potentially establishing the tumor immune niche. We engineered HSA cells to induce homozygous H1047R mutations in PIK3CA gene using CRISPR-Cas9 system. Our ongoing work is to determine if regulating PI3K pathway in the tumor cells contributes to the molecular programs that create the tumor niche of the vascular malignancy. Citation Format: Sophia Wenthe, Ashley J. Schulte, Mathew G. Angelos, Dan S. Kaufman, Jaime F. Modiano, Jong Hyuk Kim. Role of PI3K pathway in reprogramming the tumor niche of angiosarcoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO007.

Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice.

HLA Matching Status Among Patients Requiring Hematopoietic Stem Cell Transplant: The Need for a National and Regional Stem Cell Bank.

Hematopoietic stem cell transplant is a strategic treatment for many malignant and nonmalignant blood diseases. Finding an HLA-matched donor is a requirement for a successful transplantation. The aim of the current study was to explore indications, demographics, and HLA patient-donor matching status among Bahraini patients requiring this transplant. Records of 100 patients who required hematopoietic stem cell transplant at the Salmaniya Medical Complex, Ministry of Health tertiary hospital in Bahrain were retrospectively studied. Data were analyzed and compared with data from similar studies. For the 100 patients, 294 potential donors were HLA typed. Indications for transplant included malignant diseases (50%) and hereditary blood diseases (50%). For those in the 0- to 5-year age group, the main indication was acute lymphoblastic leukemia, whereas acute myeloid leukemia was the main indication for those who were >5 years old. Sex distribution showed that 55% of patients were males and 45% were females. With regard to age distribution, 22% of patients were less than 5 years old, 30% were 5 to 17 years old, and 48% were 18 years and older. Patient-donor HLA matching status was 50% HLA identical, 32% haploidentical, 15% more than haploidentical, and 3% less than haploidentical. The number of potential donors per patient ranged from 1 to 11 typed for each patient (average of 2.94 ± 1.86). The rate of finding a family member as HLA-matched donor for hematopoietic stem cell transplant in our study on Bahraini patients was higher than reports in western countries yet close to other reports from countries with almost similar family sizes. We recommend forming a national Bahrain registry in addition to a regional Eastern Mediterranean stem cell bank to increase the success rate of finding an HLA-matched donor.

Molecular Insights into the Potential of Extracellular Vesicles Released from Mesenchymal Stem Cells and Other Cells in the Therapy of Hematologic Malignancies.

Hematologic cancer encompasses the heterogeneous group of neoplasms that affect different stages of blood cell linages. Despite the significant improvements made in the new modalities of anticancer therapy, many forms of blood cancer remain untreatable, putting the afflicted patients at high risk of death. Therefore, there has been an urgent need for novel therapy to improve the clinical outcomes of patients with blood cancer. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been reported to possess an anticancer activity. This review discusses (i) the therapeutic potential of MSC-EVs against blood cancer, (ii) the possibility of using EVs from sources other than MSCs as a mean for blood cancer vaccination and drug delivery, and (iii) areas to be optimized for MSC-EV-based clinical application on blood malignancies.

The transcriptional regulation of normal and malignant blood cell development.

Development of multicellular organisms requires the differential usage of our genetic information to change one cell fate into another. This process drives the appearance of different cell types that come together to form specialized tissues sustaining a healthy organism. In the last decade, by moving away from studying single genes toward a global view of gene expression control, a revolution has taken place in our understanding of how genes work together and how cells communicate to translate the information encoded in the genome into a body plan. The development of hematopoietic cells has long served as a paradigm of development in general. In this review, we highlight how transcription factors and chromatin components work together to shape the gene regulatory networks controlling gene expression in the hematopoietic system and to drive blood cell differentiation. In addition, we outline how this process goes astray in blood cancers. We also touch upon emerging concepts that place these processes firmly into their associated subnuclear structures adding another layer of the control of differential gene expression.

Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy

Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.

Induced pluripotent stem cell models of myeloid malignancies and clonal evolution.

Reprogramming of cells from patients with genetic disorders to pluripotency is a promising avenue to understanding disease biology. A number of induced pluripotent stem cell (iPSC) models of inherited monogenic blood disorders have been reported over the past decade. However, the application of iPSCs for modeling of hematological malignancies has only recently been explored. Blood malignancies comprise a spectrum of genetically heterogeneous disorders marked by the acquisition of somatic mutations and chromosomal aberrations. This genetic heterogeneity presents unique challenges for iPSC modeling, but also opportunities to capture genetically distinct states and generate models of stepwise progression from normal to malignant hematopoiesis. Here we briefly review the current state of this field, highlighting current models of acquired pre-malignant and malignant blood disorders and clonal evolution, and challenges including barriers to reprogramming and differentiation of iPSCs into bona fide hematopoietic stem cells.

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside.

The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases—either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist’s toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.