scholarly journals Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies

2021 ◽  
Author(s):  
Timo O. Odinius ◽  
Lars Buschhorn ◽  
Celina Wagner ◽  
Richard T. Hauch ◽  
Veronika Dill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitors ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Hypereosinophilic Syndrome ◽  
Myeloproliferative Neoplasm ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Chronic Eosinophilic Leukemia ◽  
Eosinophil Granulocytes

Abstract Purpose Hypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors. Methods To understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndrome n = 18, chronic eosinophilic leukemia not otherwise specified n = 9, lymphocyte-variant hypereosinophilia n = 2, myeloproliferative neoplasm with eosinophilia n = 2, eosinophilic granulomatosis with polyangiitis n = 11, reactive eosinophilia n = 3). Results Contrary to published literature, we found no difference in the levels of the lncRNA Morrbid and its target BIM. Yet, we identified a near complete loss of expression of pro-apoptotic PUMA as well as a reduction in anti-apoptotic BCL-2. Accordingly, BCL-2 inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast, MCL1 inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful. Conclusion Our study shows that MCL1 inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

BAALC and WT1 Transcript Amount Discriminates Secondary or Reactive Eosinophilia from Idiopathic Hypereosinophilic Syndrome or Chronic Eosinophilic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5222-5222
Author(s):  
Jiannong Cen ◽  
Zixing Chen ◽  
Xiaofei Qi ◽  
Li Yao ◽  
Jun He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Fusion Gene ◽  
Hypereosinophilic Syndrome ◽  
Myeloproliferative Disorders ◽  
Hematopoietic Stem ◽  
Chronic Eosinophilic Leukemia ◽  
Relative Expression Level ◽  
Clinical Conditions ◽  
Transcript Amount

Abstract Idiopathic hypereosinophilic syndromes (HES) or chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The fusion gene FIP1L1-PDGFR alpha was identified in a subset of patients presenting with HES/CEL. In spite of this, the majority of HES/CEL patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. CD34-positive progenitor cells from bone marrow (BM) express BAALC and WT1. Overexpression of BAALC and WT1 were seen in patients with AML and ALL. In a subset of AML it marked poor prognosis, suggesting a role for BAALC or WT1 overexpression in acute leukemia. To explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on the measurement of BAALC and WT1 transcript amount. Twenty-two patients with hypereosinophilia were characterized at the molecular level and analyzed for BAALC and WT1 expression. The transcription of FIP1L1-PDGFRalpha fusion gene was detected by nested RT-PCR. The relative transcript amount of BAALC and WT1 were determined by real time PCR analyses. The FIP1L1-PDGFRalpha fusion gene expressed has been identified in bone marrow mononuclear cells of 4 cases. The relative expression level of BAALC and WT1 in these 4 cases with positive FIP1L1-PDGFRalpha fusion gene expression were 2.27(0.27–6.8) and 0.39(0.002–0.90), respectively. Whereas the relative amount of transcripts of BAALC and WT1 in 18 patients with negative FIP1L1-PDGFRalpha fusion gene were 0.069(0.015–0.11) and 0.054(0–0.34) respectively. The relative amount of transcripts of BAALC and WT1 in patients with HES/CEL were 32 times and 7 times than that in those with negative FIP1L1-PDGFRalpha fusion gene, respectively. These results clearly demonstrates that BAALC and WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

scholarly journals A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Paola Villafuerte-Gutiérrez ◽  
Montserrat López Rubio ◽  
Pilar Herrera ◽  
Eva Arranz
Keyword(s):  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Option ◽  
Myeloproliferative Neoplasm ◽  
Allogeneic Transplantation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Health Organization

Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.

scholarly journals Defective Autophagy in MPN Were Predominantly Detected in Megakaryocytes in Philadelphia Negative (Ph -) Myeloproliferative Neoplasm

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5386-5386
Author(s):  
Jen-Chin Wang ◽  
Guanfang Shi ◽  
Karan Josan ◽  
Preethi Ramachandran ◽  
Vladimir Gotlieb ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Western Blot ◽  
Cell Signaling ◽  
Mononuclear Cells ◽  
Myeloproliferative Neoplasm ◽  
Beclin 1 ◽  
Positive Staining ◽  
Rt Pcr ◽  
Peripheral Blood Mononuclear ◽  
Cytoplasmic Staining

We previously reported that autophagy was defective in classical Philadelphia negative (Ph -) Myeloproliferative Neoplasm (MPN) by demonstrating increased p62, decreased Beclin-1 by RT-PCR and Western Blot (WB) methods and decreased LC3-II by WB (ASH annual meeting poster 2018) in peripheral blood mononuclear cells. Now, we further performed immunohistochemical staining of these autophagy markers on the bone marrow biopsy specimens. Methods: Formalin-fixed and paraffin-embedded bone marrow samples were stained with primary antibodies against Beclin-1 (mouse monoclonal, Millipore), LC3B (rabbit monoclonal, Cell Signaling Technology), and p62 (mouse monoclonal, Cell Signaling Technology). The tissue sections were analyzed using VENTANA BenchMark Ultra System (Ventana Medical Systems, Inc.) according to the manufacturer's protocol. Patients who were studied included 12 essential thrombocythemia (ET), 10 polycythemia (PV), and 5 myelofibrosis (MF) (including 1 post-ET MF and 1 post-PV MF). Scoring was given based on the degree of cytoplasmic staining. Score 1 included weak cytoplasmic stain, score 2 included moderate cytoplasmic stain and score 3 was given for strong cytoplasmic staining . Results: 1) As shown in Fig1, the predominant cells which stained positive including p62, Beclin-1 , or LC3 B were mostly found on the megakaryoctes, although very few of other cell types were found to have positive staining as well 2) As shown in Table 1, the immunostaining results were in general correlated to the RT-PCR , or western blot findings that a defective autophagy was demonstrated in MPN patients with combined finding of a stronger staining in p62,and weak staining in Beclin-1 and LC3B. Conclusion: We have demonstrated defective autophagy in these Ph (-) MPN, by immunostaining of the bone marrow specimens, and demonstrating positivity for defective autophagy predominantly in megakaryocytes. Since megakaryocytes are the most important cells involved in the pathogenesis of MPN, we propose that defective autophagy in megakaryocytes play an important role in the pathogenesis of these diseases. Disclosures Wang: Incyt: Research Funding.

Abstract 241: Direct Injection of Bone Marrow Mononuclear Cells Reversed Experimental Diabetic Neuropathy by Augmenting Neovascularization and Providing Angio-neurotrophic Cytokines

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hyongbum Kim ◽  
Yong Jin Choi ◽  
Jong-seon Park ◽  
Masaaki Ii ◽  
Marcy Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diabetic Neuropathy ◽  
Neurotrophic Factors ◽  
Mononuclear Cells ◽  
Motor Nerve ◽  
Therapeutic Option ◽  
Direct Injection ◽  
Saline Group ◽  
Vasa Nervorum ◽  
Sciatic Nerves

Background: Bone marrow (BM)-derived mononuclear cells (MNCs) have been shown to effectively treat ischemic cardiovascular diseases. Recent evidence suggested that diabetic neuropathy (DN) is causally related to impaired angio-vasculogenesis in vasa nervorum and deficiency of angiogenic and neurotrophic factors. Accordingly, we sought to investigate whether DN can be ameliorated by local injection of BM-derived MNCs. Methods and Results: A severe peripheral neuropathy, characterized by significant slowing of motor nerve conduction velocities (MCV) developed 12 wks after the induction of diabetes with streptozotocin in Fisher rats (vs normal rats; 46.6±2.6 vs 32.0±2.5 m/s, P < 0.05). These rats were randomly assigned to MNC or saline injection groups (n = 9, each group) and received either 5x106 MNCs or saline intramuscularly around the sciatic nerves. In the MNC group, MCV were significantly improved within 4 wks after treatment (MNC vs Saline, 41.9±3.2 vs 32.7±2.8 m/s, P < 0.01). Microvascular circulation of sciatic nerve, measured by laser Doppler perfusion imaging was markedly increased only in the MNC group. Capillary density at 4 wks was significantly higher in the MNC group than in the saline group (68±5.9 vs 37±4.4 /cross section, P < 0.01). Robust engraftment of MNCs were observed in sciatic nerves, which sustained over 4 wks. A fraction of engrafted MNCs expressed endothelial markers suggestive of transdifferentiation into endothelial cells in the vasa nervorum. Intriguingly, a large number of the engrafted MNCs are following the course of vasa nervorum in close proximity. Real-time RT-PCR on sciatic nerves revealed that the expression of angio-neurotrophic factors were significantly increased in the MNC group compared to the saline group: VEGF (2.1 fold), FGF-2 (2.4), eNOS (18.1), Brain-derived neurotrophic factor (35.1), IGF-1 (25.5) (all P < 0.05). The protein levels were well correlated with mRNA expression levels. Conclusion: Local transplantation of BM-derived MNCs could improve experimental DN by augmenting neovascularization and increasing angiogenic and neurotrophic factors in peripheral nerves. These findings suggest that BM-MNC transplantation may represent a novel therapeutic option for treating DN.

Eosinophilia

2020 ◽  
pp. 5254-5258
Author(s):  
Peter F. Weller
Keyword(s):  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Hypereosinophilic Syndrome ◽  
Allergic Diseases ◽  
High Dose ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Drug Induced ◽  
Serological Tests ◽  
Dietary History ◽  
Hypersensitivity Vasculitis

Eosinophilia (eosinophil count >0.45 × 109/litre) is associated with some infections, some allergic diseases, and a variety of other conditions, sometimes neoplastic. Parasitic diseases—eosinophilia is a characteristic feature of infection by multicellular helminth parasites (e.g. Strongyloides stercoralis) with diagnosis typically based on geographical/dietary history, serological tests, and examination of stool or tissues for parasite forms. Other diseases—eosinophilia can be caused by the fungal disease coccidioidomycosis, and modest eosinophilia may accompany retroviral infections such as HIV and HTLV-1. Common allergic diseases—asthma, rhinitis, and atopic dermatitis are associated with modest eosinophilia. Drug reactions—these are a frequent cause of eosinophilia, at times in reactions characterized by rashes and pyrexia. More severe reactions may also manifest with (1) pulmonary eosinophilia and lung infiltrates; (2) interstitial nephritis; (3) hepatitis; (4) myocarditis; (5) drug-induced hypersensitivity vasculitis; (6) gastroenterocolitis; and (7) DRESS syndrome. Other conditions—these include (1) eosinophilic granulomatosis with polyangiitis; (2) hyper-IgE syndromes; (3) chronic myeloid leukaemia, acute myeloid leukaemia, and lymphoma; (4) a variety of pulmonary, skin, gastrointestinal, and endocrine diseases. Hypereosinophilic syndromes are defined by (1) eosinophilia (>1.5 × 109/litre) sustained over a month, (2) lack of an identifiable cause precipitating a secondary eosinophilia, and (3) symptoms and signs of organ involvement. About 30% of patients will have either a myeloproliferative condition (chronic eosinophilic leukaemia) or hypereosinophilia mediated by clonal expansion of specific T cells producing interleukin-5 (IL-5). Treatment—patients without organ damage do not require treatment. Aside from supportive care, chronic eosinophilic leukaemia may respond to tyrosine kinase inhibitors (e.g. imatinib), and nonmyeloproliferative hypereosinophilic syndrome may respond to high-dose corticosteroids, with hydroxyurea, interferon-α‎ or anti-IL-5 monoclonal antibody used in refractory cases.

scholarly journals FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nathalie Javidi-Sharifi ◽  
Jacqueline Martinez ◽  
Isabel English ◽  
Sunil K Joshi ◽  
Renata Scopim-Ribeiro ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Leukemia Cell ◽  
Marrow Stromal Cells ◽  
Leukemia Cells ◽  
Editorial Note ◽  
Development Of Resistance

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals Philadelphia Translocation in MDS: A Case Report and a Brief Review of the Literature Looking at Its Prevalence, Disease Progression, and Treatment Options

2018 ◽  
Vol 2018 ◽  
pp. 1-6
Author(s):  
Lakshmi Ramya Chelapareddy ◽  
Sandeep Sen
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Kinase Inhibitors ◽  
Treatment Guidelines ◽  
Treatment Options ◽  
Germline Mutations ◽  
Definitive Treatment ◽  
Review Of The Literature ◽  
Molecular Abnormalities ◽  
Risk Of Progression

Myelodysplastic syndrome (MDS) is a group of clonal disorders characterized by ineffective and dysplastic hematopoiesis in the bone marrow with variable risk of progression to leukemia. MDS is characterized by specific karyotypic and molecular abnormalities. The t(9 : 22) Philadelphia translocation is not a common abnormality found in MDS, and it is not included in the prognostic indices for germline mutations. There are no definitive treatment guidelines for these patients either. Here, we reviewed previously reported cases of MDS with the Philadelphia translocation with a goal to determine their prognosis and treatment options, specifically the tyrosine kinase inhibitors (TKIs).

Effects of Integrin-Linked Kinase (ILK) Inhibitor QLT0267 on Multiple Myeloma Cells and Evaluation of ILK as a Therapeutic Target in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3529-3529
Author(s):  
Thorsten Stühmer ◽  
Torsten Steinbrunn ◽  
Evelyn Grella ◽  
Ralf C. Bargou
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Therapeutic Window ◽  
Culture Dish ◽  
Peripheral Blood Mononuclear ◽  
Myeloma Cells

Abstract Multiple myeloma (MM) is a fatal plasma cell tumor that accounts for about 1% of cancers. A hallmark of the disease is its location in the bone marrow where the tumor cells receive prosurvival support from the microenvironment and cause extensive osteolytic damage. Novel drugs are currently being developed into a range of new treatment options. However, because the problems of cancer relapse and eventual selection of therapy-resistant offspring remain, additional therapeutic targets should still be investigated. ILK is a multifunctional protein that, as an adaptor and/or as a kinase, may relay adhesion- and growth factor receptor-mediated signals to downstream signaling cascades that promote growth and survival. We have analysed the expression of ILK in MM cells and have tested the effects of a novel small molecule ILK-inhibitor (QLT0267; QLT Inc., Vancouver, Canada) in MM cell lines, primary MM tumor cells and healthy cells, respectively. ILK expression at either cDNA or protein level was detectable in virtually every MM sample tested. Treatment with QLT0267 for up to 3 days resulted in extensive apoptotic death in MM cell lines (EC50 values below 10 microM in 8/9 MM cell lines tested) and in a majority of primary (anti-CD138-purified) MM samples (EC50 values below 10 microM in 8/14 primary MM samples tested). Drug treatment led to rapid decreases in the levels of phospho-STAT3, phospho-GSK3beta and total Akt protein, whereas levels of ILK and of phospho-ERK were unaffected or, in the latter case, showed a slight increase. Similar to other current pharmacologic approaches, targeting ILK may have several detrimental impacts on the signaling network that sustains MM cells. Such pleiotropic effects could prove valuable for combination treatments. The survival of peripheral blood mononuclear cells and of bone marrow stromal cells (BMSCs) at 20 microM QLT0267 was just slightly affected, indicating that the scope for establishment of a therapeutic window in MM might exist. High (20 microM) concentrations of QLT0267 gradually (and reversibly) promoted detachment of BMSCs from the culture dish, indicating that the drug might be useful to temporarily impair their effectiveness to support myeloma cells. Taken together, these experiments provide a rationale to further explore the utility of ILK-inhibition for the treatment of MM.

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