Germ line mutations associated with leukemias

Porter, Christopher C.

doi:10.1182/asheducation-2016.1.302

Cited by 48 publications

(42 citation statements)

References 54 publications

(71 reference statements)

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“…Amplification of chromosome 21, particularly the distal segment 21q22, is highly associated with acute leukemia. Germline amplification, such as in Down syndrome (trisomy 21), confers a markedly increased risk of myeloid and lymphoid leukemia 12 . In addition, somatic gain of chromosome 21 is associated with aggressive leukemias, such as iAMP21 B cell acute lymphoblastic leukemia that has multiple extra copies of 21q22 and a very poor prognosis 13 .…”

mentioning

confidence: 99%

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

et al. 2020

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Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

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confidence: 99%

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

et al. 2020

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“…A large deletion encompassing exon 2 has been reported in one pedigree . The pathogenic mutations commonly are single nucleotide substitutions and deletions leading to frameshift, missense, nonsense and splice site mutations …”

Section: Myeloid Neoplasms With Germline Etv6 Mutationmentioning

confidence: 99%

Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia

Galera

Dulau‐Florea

Calvo

2019

Int J Lab Hematology

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Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi‐ or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi‐allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.

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“…Sustained proliferation leads to a greater mutation possibility. Thus, mutation is one of the main factors in leukemia initiation and progression …”

Section: The Mechanisms Of Leukemia Pathogenesismentioning

confidence: 99%

“…Thus, mutation is one of the main factors in leukemia initiation and progression. 36 PI3K and Akt, noted oncoproteins, are essential signal transduction pathways in cancer progression. 37,38 This pathway is regulated by phosphatase and tensin homolog (PTEN), whose mutation leads to tumor development.…”

Section: Leukemia Pathogenesismentioning

confidence: 99%

Melatonin: A promising agent targeting leukemia

Shafabakhsh

Mirzaei

Asemi

2019

J of Cellular Biochemistry

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Leukemia or cancer of blood is a well‐known cancer, which affects a range of people from newborns to the very old. It is a public health problem throughout the world. By way of treatment, due to the lack of specific anticancer therapies, common treatments of leukemia lead to severe side effects. Nonspecific anticancer drugs result in inhibition of normal cell growth and thereby their necrosis. Moreover, drug resistance is an additional problem, which stands in the way of leukemia treatment. Thus, finding new treatments for leukemia is essential. Melatonin, as a natural product, has been shown to be effective in a wide variety of diseases such as coronary heart disease, schizophrenia, chronic pain, and Alzheimer's disease. In addition, melatonin levels have been observed to be altered in different cancers, such as breast cancer, colorectal cancer endometrial cancer, and hematopoetical cancers. Anticancer features of melatonin such as pro‐oxidation, apoptosis induction, antiangiogenesis property and metastasis and invasion inhibition suggest that this natural compound can be used as a potential agent in novel therapeutic strategies for cancers. Also, it has been reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggesting effectiveness in leukemia therapy. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin on leukemia models.

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Germ line mutations associated with leukemias

Cited by 48 publications

References 54 publications

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia

Melatonin: A promising agent targeting leukemia

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