scholarly journals Philadelphia-Negative MPN: A Molecular Journey, from Hematopoietic Stem Cell to Clinical Features

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1043
Author(s):  
Valentina Giai ◽  
Carolina Secreto ◽  
Roberto Freilone ◽  
Patrizia Pregno
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Myeloproliferative Neoplasms ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Factors Affecting ◽  
Thrombotic Complications ◽  
New Treatment ◽  
Disease Understanding ◽  
Generation Sequencing

Philadelphia negative Myeloproliferative Neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell diseases. MPNs show different risk grades of thrombotic complications and acute myeloid leukemia evolution. In the last couple of decades, from JAK2 mutation detection in 2005 to the newer molecular trademarks studied through next generation sequencing, we are learning to approach MPNs from a deeper perspective. Here, we intend to elucidate the important factors affecting MPN clonal advantage and the reasons why some patients progress to more aggressive disease. Understanding these mechanisms is the key to developing new treatment approaches and targeted therapies for MPN patients.

scholarly journals 2002 – GENETIC PREDISPOSITION TO MYELOPROLIFERATIVE NEOPLASMS IMPLICATES HEMATOPOIETIC STEM CELL BIOLOGY

2020 ◽  
Vol 88 ◽  
pp. S27
Author(s):  
Satish Nandakumar ◽  
Erik Bao ◽  
Xiaotian Liao ◽  
Alexander Bick ◽  
Juha Karjalainen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Genetic Predisposition ◽  
Cell Biology ◽  
Myeloproliferative Neoplasms ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

scholarly journals Predictors of neutralizing antibody response to BNT162b2 vaccination in allogeneic hematopoietic stem cell transplant recipients

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lorenzo Canti ◽  
Stéphanie Humblet-Baron ◽  
Isabelle Desombere ◽  
Julika Neumann ◽  
Pieter Pannus ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Neutralizing Antibody ◽  
Healthy Adults ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Factors Affecting

Abstract Background Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated. Methods Forty allo-HCT recipients were included in a study of immunization with BNT162b2 mRNA vaccine at days 0 and 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD) were assessed at days 0, 21, 28, and 49 while neutralizing Ab against SARS-CoV-2 wild type (NT50) were assessed at days 0 and 49. Results observed in allo-HCT patients were compared to those obtained in 40 healthy adults naive of SARS-CoV-2 infection. Flow cytometry analysis of peripheral blood cells was performed before vaccination to identify potential predictors of Ab responses. Results Three patients had detectable anti-RBD Ab before vaccination. Among the 37 SARS-CoV-2 naive patients, 20 (54%) and 32 (86%) patients had detectable anti-RBD Ab 21 days and 49 days postvaccination. Comparing anti-RBD Ab levels in allo-HCT recipients and healthy adults, we observed significantly lower anti-RBD Ab levels in allo-HCT recipients at days 21, 28 and 49. Further, 49% of allo-HCT patients versus 88% of healthy adults had detectable NT50 Ab at day 49 while allo-HCT recipients had significantly lower NT50 Ab titers than healthy adults (P = 0.0004). Ongoing moderate/severe chronic GVHD (P < 0.01) as well as rituximab administration in the year prior to vaccination (P < 0.05) correlated with low anti-RBD and NT50 Ab titers at 49 days after the first vaccination in multivariate analyses. Compared to healthy adults, allo-HCT patients without chronic GVHD or rituximab therapy had comparable anti-RBD Ab levels and NT50 Ab titers at day 49. Flow cytometry analyses before vaccination indicated that Ab responses in allo-HCT patients were strongly correlated with the number of memory B cells and of naive CD4+ T cells (r > 0.5, P < 0.01) and more weakly with the number of follicular helper T cells (r = 0.4, P = 0.01). Conclusions Chronic GVHD and rituximab administration in allo-HCT recipients are associated with reduced Ab responses to BNT162b2 vaccination. Immunological markers could help identify allo-HCT patients at risk of poor Ab response to mRNA vaccination. Trial registration The study was registered at clinicaltrialsregister.eu on 11 March 2021 (EudractCT # 2021-000673-83).

Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 41 (03) ◽  
pp. 197-205
Author(s):  
Franziska C. Zeeh ◽  
Sara C. Meyer
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mutational Analysis ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Standard Of Care ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Therapeutic Decisions ◽  
Jak2 Inhibitors

AbstractPhiladelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

scholarly journals JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F–positive essential thrombocythemia

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1528-1538 ◽  
Author(s):  
Juan Li ◽  
Dominik Spensberger ◽  
Jong Sook Ahn ◽  
Shubha Anand ◽  
Philip A. Beer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Essential Thrombocythemia ◽  
Cell Function ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Transgenic Models ◽  
Disease Phenotype ◽  
Hematopoietic Stem

The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.

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