MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development

Voit, Richard A.; Sankaran, Vijay G.

doi:10.1007/s10875-023-01545-0

Cited by 9 publications

(1 citation statement)

References 48 publications

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“…The del(3)(q21) involves the loss of important genes such as GATA2, 7 BCL6 8 and MECOM . 9 The del(3q) was also present at the abnormal cytogenetic clone detected at diagnosis with other chromosomal abnormalities involving important genes such as MYB in del(6)(q21); c-MYC in +8; and ETV6 in del(12)(p11). It is interesting to note the high genomic instability in this patient, who also acquired the gain of these abnormal chromosomes, resulting in chromosome derivatives.…”

Section: To the Editormentioning

confidence: 98%

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in a Child with Myelodysplastic Neoplasm with Complex Karyotype and ETV6 Variant: Challenges in Treatment

Almeida Antônio de Kós,

Lamim Lovatel,

Barbosa Tavares

et al. 2024

Mediterr J Hematol Infect Dis

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelodysplastic neoplasm (MDS). Nevertheless, disease relapse is the main cause of treatment failure. Due to the rarity of childhood MDS (cMDS), there are few studies showing the impact of cytogenetic alterations and genetic variants on outcomes of allo-HSCT, mainly focusing on clonal chromosomal evolution (CCE) during relapse post-transplant. Here, we describe a 3-year-old boy with cMDS-IB, who evolved to MDS/AML. At diagnosis, the patient showed a complex karyotype with chromosomal abnormalities not yet reported together in the same clone, and likely a pathogenic variant in the ETV6 gene. The patient was treated with HLA-matched sibling HSCT, but unfortunately relapsed after HSCT with clonal cytogenetic evolution. This unfavorable outcome suggests that the treatment of pediatric MDS associated with predictive factors of poor prognosis, such as complex karyotype and ETV6 variant remains a challenge.

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Section: To the Editormentioning

confidence: 98%

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in a Child with Myelodysplastic Neoplasm with Complex Karyotype and ETV6 Variant: Challenges in Treatment

Almeida Antônio de Kós,

Lamim Lovatel,

Barbosa Tavares

et al. 2024

Mediterr J Hematol Infect Dis

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Phenotypic heterogeneity associated with a novel MECOM variant: Mild thrombocytopenia to hydrops fetalis

Jaspersen,

Stacy,

McGlynn

et al. 2024

Pediatric Blood & Cancer

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MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2

Iida,

Nakanishi,

Nakahara

et al. 2024

Preprint

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MECOM is a nuclear transcription factor essential for the proliferation of hematopoietic stem cells (HSCs) and myeloid leukemia cells. MECOM contains N- and C-terminal zinc finger domains (ZFDs) and binding motifs for the corepressor CtBP to regulate gene expression. Recent studies have shown that germlineMECOMvariants are associated with thrombocytopenia, radioulnar synostosis, and bone marrow failure, collectively termed MECOM-associated syndromes. Although the mutations are clustered in the C-terminal ZFD, how these mutations affect MECOM function has remained unclear. In addition, the individual genes and pathways regulated by MECOM are less well understood. In this study, we showed that the C-terminal ZFD is a major DNA-binding domain of MECOM and that the disease-associated mutations abolish the DNA-binding ability. We also found that MECOM functionally antagonizes GATA2 through the C-terminal ZFD-mediated DNA binding and CtBP interaction, thereby promoting myeloid leukemogenesis while inhibiting mast cell differentiation. Furthermore, we generated mutant MECOM knockin mice harboring a C-terminal ZFD mutation that recapitulate several features of MECOM-associated syndromes, including HSC and B-cell reduction. Our study demonstrates that C-terminal ZFD mutations are loss-of-function mutations with reduced DNA-binding ability, reveals the critical role of MECOM in inhibiting GATA2, and provides a novel mouse model for MECOM-associated syndromes.

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MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development

Cited by 9 publications

References 48 publications

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in a Child with Myelodysplastic Neoplasm with Complex Karyotype and ETV6 Variant: Challenges in Treatment

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in a Child with Myelodysplastic Neoplasm with Complex Karyotype and ETV6 Variant: Challenges in Treatment

Phenotypic heterogeneity associated with a novel MECOM variant: Mild thrombocytopenia to hydrops fetalis

MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2

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