Aetiology and outcomes of secondary myelofibrosis occurring in the context of inherited platelet disorders: A single institutional study of four patients

Saliba, Antoine N.; Ferrer, Alejandro; Gangat, Naseema; Pruthi, Rajiv K.; Tefferi, Ayalew; Higgins, Alexandra; Bezerra, Evandro D.; Buglioni, Alessia; Salama, Mohamed E.; Klee, Eric W.; Vairo, Filippo Pinto e; Mangaonkar, Abhishek A.; Majerus, Julie A.; Chen, Dong; Patnaik, Mrinal M.

doi:10.1111/bjh.16897

Cited by 9 publications

(16 citation statements)

References 16 publications

(31 reference statements)

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“…( 41 ) Based on our findings, female patients carrying homozygous null and loss‐of‐function mutations in MPIG6B should be closely monitored for developing of splenomegaly and osteosclerosis as they age. ( 7,8,42,43 ) Our data suggest that these patients can develop complications from osteosclerosis later in life and that a decrease in estrogen level may improve their quality of life.…”

Section: Discussionmentioning

confidence: 79%

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Stavnichuk

Tauer

Nagy

et al. 2020

Journal of Bone and Mineral Research

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Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss‐of‐function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b‐B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b−/−) mice. Although male and female Mpig6b−/− mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b−/− mice developed progressive splenomegaly starting at 8 weeks of age. Micro–computed tomography (μCT) of femurs showed that female Mpig6b−/− mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b−/− mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10‐week‐old female Mpig6b−/− mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b−/− mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b−/− mice also demonstrated improvement in spleen weight compared to sham‐operated Mpig6b−/− mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte‐driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Section: Discussionmentioning

confidence: 79%

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Stavnichuk

Tauer

Nagy

et al. 2020

Journal of Bone and Mineral Research

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“… 10 Genetic diagnosis may be approached by Sanger sequencing of the NBEAL2 gene, when the diagnosis of GPS is suspected based on the phenotypic features, or by high-throughput sequencing, including gene panels for inherited platelet disorders 19 or whole-exome sequencing. 17 …”

Section: Spectrum Of Nbeal2 Mutationsmentioning

confidence: 99%

A Deep Dive into the Pathology of Gray Platelet Syndrome: New Insights on Immune Dysregulation

Glembotsky

Luca

Heller

2021

JBM

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The gray platelet syndrome (GPS) is a rare platelet disorder, characterized by impaired alpha-granule biogenesis in megakaryocytes and platelets due to NBEAL2 mutations. Typical clinical features include macrothrombocytopenia, bleeding and elevated vitamin B12 levels, while bone marrow fibrosis and splenomegaly may develop during disease progression. Recently, the involvement of other blood lineages has been highlighted, revealing the role of NBEAL2 outside the megakaryocyte-platelet axis. Low leukocyte counts, decreased neutrophil granulation and impaired neutrophil extracellular trap formation represent prominent findings in GPS patients, reflecting deranged innate immunity and associated with an increased susceptibility to infection. In addition, low numbers and impaired degranulation of NK cells have been demonstrated in animal models. Autoimmune diseases involving different organs and a spectrum of autoantibodies are present in a substantial proportion of GPS patients, expanding the syndromic spectrum of this disorder and pointing to dysregulation of the adaptive immune response. Low-grade inflammation, as evidenced by elevation of liver-derived acute-phase reactants, is another previously unrecognized feature of GPS which may contribute to disease manifestations. This review will focus on the mechanisms underlying the pathogenesis of blood cell abnormalities in human GPS patients and NBEAL2-null animal models, providing insight into the effects of NBEAL2 in hemostasis, inflammation and immunity.

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“…Patients with disease-causing variants within MPIG6B present(ed) with congenital macrothrombocytopenia, mild-to-moderate bleeding diathesis, focal myelofibrosis and atypical MKs, however the underlying causes of the disease have remained unclear. [3][4][5][6][7] Our results demonstrate a previously unrecognized key function of G6b-B in MK maturation by regulating cell size, DMS development, receptor levels and gene expression. These findings thus challenge the previous concept, which proposed a rather unaffected development of G6b-B deficient MKs 2,4,8,20 , and provide an unexpected mechanistic explanation for the severe macrothrombocytopenia in Mpig6b mut mice, as a direct consequence of an overall MK maturation defect.…”

Section: Mpig6b -/Mice Display Less Mature Mksmentioning

confidence: 70%

“…2 Deletion of the Mpig6b locus in mice results in macrothrombocytopenia and myelofibrosis, 2 which was recently recapitulated in humans with disease-causing null-variants within MPIG6B. [3][4][5][6][7] It was hypothesized that G6b-B affects a terminal step in platelet production, 2,8 however, mechanistic insights are yet lacking. By characterizing a spontaneous Mpig6b mutant together with a newly generated Mpig6b-null mouse line we provide unexpected experimental evidence that establishes G6b-B as a central regulator for MK maturation, which can explain the complex phenotype of these mice.…”

Section: Introductionmentioning

confidence: 99%

G6b-B regulates an essential step in megakaryocyte maturation

Becker

Nagy

Manukjan

et al. 2021

Preprint

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G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entire Mpig6b locus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations in MPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of the Mpig6b locus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange, Mpig6bmut mice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developed Mpig6b null mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.

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Aetiology and outcomes of secondary myelofibrosis occurring in the context of inherited platelet disorders: A single institutional study of four patients

Abstract: Response and progression-free survival according to planned treatment duration in patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in the phase III ASPIRE study.

Cited by 9 publications

References 16 publications

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

A Deep Dive into the Pathology of Gray Platelet Syndrome: New Insights on Immune Dysregulation

G6b-B regulates an essential step in megakaryocyte maturation

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