Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

Ge, Zheng; Li, Min; Zhao, Gang; Ling, Xiao; Gu, Yan; Zhou, Xilian; Yu, Michael D; Li, Jianyong; Dovat, Sinisa; Song, Chunhua

doi:10.3892/ol.2016.4993

Cited by 16 publications

(21 citation statements)

References 27 publications

(33 reference statements)

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“…Although we did not detect DNM2 mutations in adults with B-cell ALL (data not shown) we found significantly higher expression of DNM2 . In contrast, we detected DNM2 mutations in 4 adults with T-cell ALL27. High DNM2 expression is also seen in subjects with T-cell ALL, but DNM2 expression in subjects with mutations is difficult to evaluate because of few subjects.…”

Section: Discussionmentioning

confidence: 56%

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Han

et al. 2016

Sci Rep

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Dynamin-2 (DNM2) is a GTPase essential for intracellular vesicle formation and trafficking, cytokinesis and receptor endocytosis. Mutations in DNM2 are common in early T-cell precursor acute lymphoblastic leukemia. However, DNM2 expression in other types of ALL are not reported. We studied DNM2 mRNA level in adults with B- and T-cell ALL. We found DNM2 is more highly expressed compared with normals in both forms of ALL. High DNM2 expression is associated with some clinical and laboratory features, inferior outcomes and with leukaemia cell proliferation. We also found Ikaros directly binds the DNM2 promoter and suppresses DNM2 expression. Consequently IKZF1 deletion is associated with high DNM2 expression. Conversely, casein kinase-2 (CK2)-inhibitor increases Ikaros function thereby inhibiting DNM2 expression. Inhibiting DNM2 suppresses proliferation of leukemia cells and synergizes with CK2 inhibition. Our data indicate high DNM2 expression is associated with Ikaros dysregulation and may be important in the development of B-ALL.

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Section: Discussionmentioning

confidence: 56%

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Han

et al. 2016

Sci Rep

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“…DNM2 regulates a variety of cellular processes through CME and mutations have been well documented in the pathogenesis of CNM and CMT although mutations in the GTPase domain have not been identified in either disease. However, in the setting of cancer, recurrent mutations in all DNM2 domains including the GTPase domain are found in T‐cell acute lymphoblastic leukaemia (Zhang et al , ; Neumann et al , ; Ge et al , ). Consequently, when Dnm2 V235G animals were bred onto the Lmo2 oncogenic background, T‐ALL development was accelerated in vivo with enhanced IL7 receptor signalling due to impaired CME (Tremblay et al , ).…”

Section: Discussionmentioning

confidence: 99%

Loss of Dynamin 2 GTPase function results in microcytic anaemia

et al. 2017

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In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytic hypochromia caused by a V235G missense mutation in Dynamin 2 (Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific and have been implicated in four forms of human diseases: centronuclear myopathy, Charcot-Marie Tooth neuropathy and, more recently, T-cell leukaemia and Hereditary Spastic Paraplegia, but red cell abnormalities have not been reported to date. The V235G mutation lies within a crucial GTP nucleotide-binding pocket of Dnm2, and resulted in defective GTPase activity and incompatibility with life in the homozygous state. Dnm2 is an essential mediator of clathrin-mediated endocytosis, which is required for the uptake of transferrin (Tf) into red cells for incorporation of haem. Accordingly, we observed significantly reduced Tf uptake by Dnm2 cells, which led to impaired endosome formation. Despite these deficiencies, surprisingly all iron studies were unchanged, suggesting an unexplained alternative mechanism underlies microcytic anaemia in Dnm2 mice. This study provides the first in vivo evidence for the requirements of Dnm2 in normal erythropoiesis.

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“…Also, in Table 2, we found some genes related to CNS leukemia. DNM2 mutation was found to be related with oncogenesis in ALL 19 . A KDR mutation has been reported previously in angiosarcomas 20 .…”

Section: Discussionmentioning

confidence: 99%

A Case of Acute Lymphocytic Leukaemia with t(3;13) and Central Nervous System Leukemia after Allogenic Cord Blood Transplantation

Hong

Huang

et al. 2019

Cell Med

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Background:Acute lymphoblastic leukemia (ALL) is a neoplastic cancer characterized by clonal expansion of leukemic cells in lymph organs and bone marrow. Lots of kinds of different chromosomal translocations can be found in those leukemic cells. However, the role of abnormal chromosomes and genes in leukemogenesis is not yet fully understood. Identifying new chromosomal translocations can facilitate a better understanding of pathogenesis of this disease.Case presentation:We report a rare case of acute lymphocytic leukaemia with t(3;13)(q29, q21). The patient was diagnosed pre-B-ALL with no abnormal chromosomal or gene fusion and achieved complete remission (CR) after induction chemotherapy; 10 months later, she relapsed in the consolidation, with cytogenetics tests showing 46, XX, t(3;13)(q29, q21). Given no CR after two chemotherapy regimens, the patient received salvage cord blood transplantation. Regular intrathecal methotrexate was applied to prevent central nervous system leukemia. Good graft versus leukemia was induced by daily injection of a low dose of IL-2 2 months post-transplantation. Minimal residual disease negativity was maintained until central nervous system (CNS) leukemia was found 8 months after transplantation. A whole exome sequencing was performed. Nine driver mutation genes and seven tumor genes were found.Conclusions:We highly suspect that the relapse in the CNS after transplantation is associated with a rare chromosomal translocation.

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Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

Cited by 16 publications

References 27 publications

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Loss of Dynamin 2 GTPase function results in microcytic anaemia

A Case of Acute Lymphocytic Leukaemia with t(3;13) and Central Nervous System Leukemia after Allogenic Cord Blood Transplantation

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