The role of HOX genes in normal hematopoiesis and acute leukemia

Alharbi, Raed; Pettengell, Ruth; Pandha, Hardev; Morgan, Richard

doi:10.1038/leu.2012.356

Cited by 288 publications

(270 citation statements)

References 128 publications

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“…This is fully compatible with the involvement of the HoxA family in stem cell expansion and leukemogenesis. [35][36][37][38] Using RNA interference-based functional screening, Cellot et al 39 identified the H3K4 demethylase JARID1B as a negative regulator of HSC functions among the Jumonji domain-containing family of histone demethylases. The shRNA-mediated knockdown of JARID1B leads to the in vitro expansion of HSCs, which is accompanied by the upregulation of HoxA7, HoxA9, and HoxA10, with preserved long-term reconstitution potential.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Wada

Koyama

Kikuchi

et al. 2015

Blood

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Key Points• LSD1 is barely expressed in normal hematopoietic stem cells, but is overexpressed in leukemias especially those of a T-cell origin.• LSD1 overexpression forms preleukemic stem cells with an increased self-renewal potential in a transgenic mice model.Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/ lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after g-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease. (Blood. 2015;125(24):3731-3746)

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Section: Discussionmentioning

confidence: 99%

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Wada

Koyama

Kikuchi

et al. 2015

Blood

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“…Hox family regulates genes which control the anterior-posterior body plan and assign tissue fate in human (61). Dysregulation of Hoxa9 has been found in more than 50% of AML patients and highly predicts worse survival (62).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

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“…[11][12][13][14][15][16] One such approach is to express a HOX protein that confers a benign proliferative advantage to the modified cells over the non-transduced cells in vivo. 15,17,18 HOXB4 was the first HOX family member found to enhance the expansion of human and mouse HSCs by promoting self-renewal divisions without losing stemness. 19,20 Certain fusion proteins of HOXB4 have also been shown to induce expansion of hematopoietic stem cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

et al. 2017

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The role of HOX genes in normal hematopoiesis and acute leukemia

Abstract: 20The HOX genes are a highly conserved family of homeodomain-containing 21 transcription factors that specify cell identity in early development and, subsequently,

Cited by 288 publications

References 128 publications

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

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