scholarly journals The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm

Blood ◽  
2014 ◽  
Vol 124 (26) ◽  
pp. 3956-3963 ◽  
Author(s):  
Veena Sangkhae ◽  
S. Leah Etheridge ◽  
Kenneth Kaushansky ◽  
Ian S. Hitchcock
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Hematopoietic Stem ◽  
Thrombopoietin Receptor ◽  
Key Points

Key Points MPL is essential for the development of JAK2V617F-positive myeloproliferative neoplasms in vivo. Ablation or reduction of Mpl significantly reduces the pool of neoplastic hematopoietic stem cells.

scholarly journals The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN

2021 ◽  
Vol 11 ◽  
Author(s):  
Jerry L. Spivak ◽  
Alison R. Moliterno
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Therapeutic Target ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Thrombopoietin Receptor

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis share driver mutations that either activate the thrombopoietin receptor, MPL, or indirectly activate it through mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, although the myeloproliferative neoplasms are classified as neoplasms because they are clonal hematopoietic stem cell disorders, the mutations affecting MPL or JAK2 are gain-of-function, resulting in increased production of normal erythrocytes, myeloid cells and platelets. Constitutive JAK2 activation provides the basis for the shared clinical features of the myeloproliferative neoplasms. A second molecular abnormality, impaired posttranslational processing of MPL is also shared by these disorders but has not received the recognition it deserves. This abnormality is important because MPL is the only hematopoietic growth factor receptor expressed in hematopoietic stem cells; because MPL is a proto-oncogene; because impaired MPL processing results in chronic elevation of plasma thrombopoietin, and since these diseases involve normal hematopoietic stem cells, they have proven resistant to therapies used in other myeloid neoplasms. We hypothesize that MPL offers a selective therapeutic target in the myeloproliferative neoplasms since impaired MPL processing is unique to the involved stem cells, while MPL is required for hematopoietic stem cell survival and quiescent in their bone marrow niches. In this review, we will discuss myeloproliferative neoplasm hematopoietic stem cell pathophysiology in the context of the behavior of MPL and its ligand thrombopoietin and the ability of thrombopoietin gene deletion to abrogate the disease phenotype in vivo in a JAK2 V617 transgenic mouse model of PV.

scholarly journals Erk1 and Erk2 are required for maintenance of hematopoietic stem cells and adult hematopoiesis

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3594-3598 ◽  
Author(s):  
Gordon Chan ◽  
Shengqing Gu ◽  
Benjamin G. Neel
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Key Points

Key Points Erk1/2 are required for the maintenance of hematopoietic stem cells and immature progenitors in vivo.

scholarly journals Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 327-335 ◽  
Author(s):  
Edwin Chen ◽  
Rebekka K. Schneider ◽  
Lawrence J. Breyfogle ◽  
Emily A. Rosen ◽  
Luke Poveromo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Competitive Advantage ◽  
Disease Progression ◽  
Myeloproliferative Neoplasms ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Promote Disease Progression

Key Points Tet2 loss of function confers a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells. Jak2V617F expression and Tet2 loss generate distinct and nonoverlapping transcriptional programs in hematopoietic stem cells.

scholarly journals Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3437-3446 ◽  
Author(s):  
Takeshi Ueda ◽  
Akiko Nagamachi ◽  
Keiyo Takubo ◽  
Norimasa Yamasaki ◽  
Hirotaka Matsui ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Metabolic Activation ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Enhanced Expression ◽  
Bona Fide

Key Points Fbxl10 is a bona fide oncogene in vivo. Fbxl10 overexpression in HSCs induces mitochondrial metabolic activation and enhanced expression of Nsg2.

scholarly journals Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates

Blood ◽  
2016 ◽  
Vol 127 (20) ◽  
pp. 2416-2426 ◽  
Author(s):  
Christopher W. Peterson ◽  
Jianbin Wang ◽  
Krystin K. Norman ◽  
Zachary K. Norgaard ◽  
Olivier Humbert ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Nonhuman Primates ◽  
Large Animal Model ◽  
Large Animal ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Specific Manner

Key Points This study is the first to show that genome-editing approaches can modify multilineage, long-term repopulating cells in a large animal model. We demonstrate that the persistence of genome-edited hematopoietic stem cells can be tracked in vivo in a mutation-specific manner.

scholarly journals Myeloproliferative neoplasm stem cells

Blood ◽  
2017 ◽  
Vol 129 (12) ◽  
pp. 1607-1616 ◽  
Author(s):  
Adam J. Mead ◽  
Ann Mullally
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Selective Advantage ◽  
Myeloid Differentiation ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Disease Phenotypes ◽  
Thrombopoietin Receptor

Abstract Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: JAK2, CALR, or MPL. The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells. Despite common biological features, MPNs display diverse disease phenotypes as a result of both constitutional and acquired factors that influence MPN stem cells, and likely also as a result of heterogeneity in the HSC in which MPN-initiating mutations arise. As the MPN clone expands, it exerts cell-extrinsic effects on components of the bone marrow niche that can favor the survival and expansion of MPN stem cells over normal HSC, further sustaining and driving malignant hematopoiesis. Although developed as targeted therapies for MPNs, current JAK2 inhibitors do not preferentially target MPN stem cells, and as a result, rarely induce molecular remissions in MPN patients. As the understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances, this will help facilitate the development of therapies that preferentially target MPN stem cells over normal HSC.

scholarly journals Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms

Blood ◽  
2020 ◽  
Author(s):  
Kotaro Shide ◽  
Takuro Kameda ◽  
Ayako Kamiunten ◽  
Yoshinori Ozono ◽  
Yuki Tahira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Cell Activity ◽  
Extramedullary Hematopoiesis ◽  
The Self ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Deficient Mice

Mutations in JAK2, MPL, or CALR are detected in more than 80% of myeloproliferative neoplasm (MPN) patients and are thought to play a driver role in MPN pathogenesis via autosomal activation of the JAK-STAT signaling cascade. Mutant CALR binds to MPL, activates downstream MPL signaling cascades, and induces essential thrombocythemia in mice. However, embryonic lethality of Calr-deficient mice precludes determination of a role for CALR in hematopoiesis. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr-deficient mice. CALR deficiency had little effect on the leukocyte count, hemoglobin levels, or platelet count in peripheral blood. However, Calr-deficient mice showed some hematopoietic properties of MPN, including decreased erythropoiesis and increased myeloid progenitor cells in the bone marrow, and extramedullary hematopoiesis in the spleen. Transplantation experiments revealed that Calr haploinsufficiency promoted the self-renewal capacity of hematopoietic stem cells. We generated CALRdel52 mutant transgenic mice with Calr haploinsufficiency as a model that mimics human MPN patients and found that Calr haploinsufficiency restored the self-renewal capacity of hematopoietic stem cells damaged by CALR mutations. Only recipient mice transplanted with Lineage－Sca1+c-kit+ cells harboring both CALR mutation and Calr haploinsufficiency developed MPN in competitive conditions, showing that CALR haploinsufficiency was required for the onset of CALR-mutated MPNs.

Notch signals are required for in vitro but not in vivo maintenance of human hematopoietic stem cells and delay the appearance of multipotent progenitors

Blood ◽  
2014 ◽  
Vol 123 (8) ◽  
pp. 1167-1177 ◽  
Author(s):  
Patricia Benveniste ◽  
Pablo Serra ◽  
Dzana Dervovic ◽  
Elaine Herer ◽  
Gisele Knowles ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Immune Reconstitution ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Multipotent Progenitors ◽  
Key Points

Key Points Notch signals expand human HSC (CD90low) cells in vitro and delay the expansion of CD45RAint and CD45RAhi cells in vitro. HSCs expanded in vitro are equal to ex vivo CD90low cells in immune reconstitution.

scholarly journals In vivo time-lapse imaging shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells

Blood ◽  
2014 ◽  
Vol 124 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Narges M. Rashidi ◽  
Mark K. Scott ◽  
Nico Scherf ◽  
Axel Krinner ◽  
Jens S. Kalchschmidt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Acute Infection ◽  
Time Lapse ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Time Lapse Imaging ◽  
Bone Marrow Niches

Key Points Normally, engrafting HSCs reside and oscillate within confined bone marrow niches. HSCs harvested from mice bearing acute infection are migratory and interact with larger niches.

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