The new thrombopoietic agenda: Impact on leukemias and MDS

Bussel, James B.

doi:10.1016/j.beha.2014.10.012

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…Our results suggest that the use of TPO or TPO mimetics to rescue MDM2 antagonist-mediated thrombocytopenia would be difficult. However, only in vivo treatment may answer this question since TPO mimetics such as Romiplostim or Elthrombopag lead to substantial increased platelets in immune thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) or other cancer-related thrombocytopenia, even when a MK apoptosis is part of the mechanism of the thrombocytopenia [22, 23]. …”

Section: Discussionmentioning

confidence: 99%

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

et al. 2016

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TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.

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Section: Discussionmentioning

confidence: 99%

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

et al. 2016

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“…However, because of the discovery of induced antibodies that neutralize TPO and cause thrombocytopenia, its clinical development was stopped immediately [9]. The development of new types of TPO was subsequently continued, and at present, three drugs-romiplostim (RP), eltrombopag, and avatrombopag-are available as therapies for idiopathic thrombocytopenic purpura (ITP) [10][11][12]. Our previous studies showed that the RP completely rescued mice exposed to lethal total-body irradiation (TBI), suggesting that RP may not only promote hematopoiesis in various organs in irradiated individuals but also mitigate the dysfunction or regenerate the original function in multiple organs [13].…”

Section: Introductionmentioning

confidence: 99%

An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice

2022

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The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only completely rescues irradiated mice but also shows mitigative effects on their hematopoiesis and multiple organ injury, including that of the lung, bone marrow, small intestine, and liver. However, the mechanism by which RP functions as a radiomitigator remains unclear. In the present study, we applied a metabolomics approach, which has the ability to reflect the status of an organism directly and accurately, helping to elucidate the biology of treatment responses. Our results showed that the disruption of several metabolites and pathways in response to total body irradiation was partially corrected by RP administration. Notably, RP-corrected metabolites and pathways have been reported to be indicators of DNA damage and lung, bone marrow, small intestine, and liver injury. Taken together, the present findings suggested that the radiomitigative effect of RP is partially involved in the recovery of organ injury, and the identified metabolites may be a useful biomarker of the survival likelihood following radiation exposure.

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“…Most patients have the complications of low platelet count in the circulation and abnormalities of megakaryocytes in the bone marrow 18 , 19 and these 2 features are associated with the progression and prognosis of the disease. 20 , 21 Some recent case reports have reported morphologic alterations of megakaryocytes in bone marrow from MDS patients. 22 , 23…”

Section: Resultsmentioning

confidence: 99%

Ultrastructural alterations of megakaryocytes in thrombocytopenia: A review of 43 cases

Eyden

Dong

et al. 2021

Blood Science

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Thrombocytopenia is a frequent occurrence in a variety of hematopoietic diseases; however, the details of the mechanism leading to low platelet count remain elusive. Megakaryocytes are a series of progenitor cells responsible for the production of platelets. Alterations in megakaryocytes in the bone marrow are a causative factor resulting in thrombocytopenia in varied diseases. Based on ultrastructural analysis of incidentally encountered megakaryocytes in 43 patients with blood diseases marked by low platelet counts, electron micrographs demonstrated that aberrant megakaryocytes predominated in idiopathic thrombocytopenic purpura, aplastic anemia, and myelodysplastic syndrome; autophagy, apoptosis, and cellular damage in megakaryocytes were a prominent feature in aplastic anemia. On the other hand, poorly differentiated megakaryocytes predominated in acute megakaryoblastic leukemia (AMKL) although damaged megakaryocytes were seen in non-AMKL acute leukemia. This paper documents the ultrastructural alterations of megakaryocytes associated with thrombocytopenia and reveals distinctive features for particular blood diseases. A comment is made on future avenues of research emphasizing membrane fusion proteins.

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The new thrombopoietic agenda: Impact on leukemias and MDS

Cited by 7 publications

References 10 publications

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice

Ultrastructural alterations of megakaryocytes in thrombocytopenia: A review of 43 cases

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