<i>HOX</i>
 gene expression in phenotypic and genotypic subgroups and low <i>HOXA</i>
 gene expression as an adverse prognostic factor in pediatric ALL

Starková, Júlia; Zámostná, Blanka; Mejstříková, Ester; Krejčí, Roman; Drabkin, Harry A.; Trka, Jan

doi:10.1002/pbc.22749

Cited by 26 publications

(20 citation statements)

References 43 publications

(52 reference statements)

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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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“…For the remaining groups, the prognosis is much worse, as indicated by 5‐year OS of 33% (±19%) in LYL1 ‐overexpressing group, 43% (±19%) in TAL1/LMO2 subtype and 30% (±24%) in TLX3 group. A recent study on HOXA overexpression demonstrated that it is related to an excellent prognosis with 6‐year relapse free survival (RFS) of 100% (patient HOXA expression above 75th percentile) (Starkova et al , 2010).…”

Section: Gene Expression Profilesmentioning

confidence: 99%

T‐cell acute lymphoblastic leukaemia: recent molecular biology findings

et al. 2011

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Summary For many years, T‐cell acute lymphoblastic leukaemia (T‐ALL) has been considered and treated as a single malignancy, but divergent outcomes in T‐ALL patients receiving uniform treatment protocols encouraged intensive research on the molecular biology of this disease. Recent findings in the field demonstrate that T‐ALL is much more heterogeneous than originally believed and extremely diverse outcomes of patients require refinement of T‐ALL classification, leading to subtype‐specific adjustment of treatment. Many different biological features of T‐ALL blast cells have recently been found to contribute to disease development and patient outcome and their analysis could potentially be introduced into improved diagnostics and classification of the disease. This review focuses on five key issues of T‐ALL biology: chromosome aberrations, gene expression profiles, gene mutations, DNA methylation patterns, and immunoglobulin/T cell receptor (Ig/TCR) gene rearrangements. Additionally, molecular monitoring of minimal residual disease, by far the most reliable independent prognostic factor in T‐ALL, has been highlighted in the context of Ig/TCR gene rearrangements. Translation of this biological information into better prognostic classification and more effective treatment should lead to improvement of outcome in T‐ALL patients.

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“…26,27 Thus, HIST1H2BD and HIST1H1E may be added to the growing list of acute leukemia-associated genes, for example DNMT3, EZH2, HOX family, and MLL, that 13 contribute to the leukemogenic process through deregulated CpG methylation or histone modification. [28][29][30][31] Among the other recurrent gene targets, most -CDKN2A, EBF1, ETV6, IKZF1, PAX5, RAG1, and TBL1XR1 -have been thoroughly discussed previously. 17,19,27,32,33 However, three of the presently identified gene targets, ADD3, ATP10A and PAN3, have been less emphasized in previous studies.…”

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confidence: 99%

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

et al. 2013

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, Castor, A., Behrendtz, M., Biloglav, A., Forestier, E., Paulsson, K., & Johansson, B. (2014). Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia, 28(2), 302-310. DOI: 10.1038DOI: 10. /leu.2013 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate analyses, age (≥10 years), WBC counts (>100 x 10 9 /l), t(9;22)(q34;q11), MLL rearrangements, nearhaploidy, and deletions of ATP10A, IKZF1, SPRED1, and the pseudoautosomal 1 regions on Xp/Yp were significantly associated with decreased 10-year event-free survival, with IKZF1 abnormalities being an independent risk factor in multivariate analysis irrespective of risk group. High age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival. Thus, analyses of these genes provide clinically important information.

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HOX gene expression in phenotypic and genotypic subgroups and low HOXA gene expression as an adverse prognostic factor in pediatric ALL

Abstract: HOX gene RNA expression cannot discriminate leukemia subgroups or relative maturity of leukemic cells. However, HOXA RNA expression correlates with prognosis, and particular HOX genes are expressed in specific genotypically characterized subgroups.

Cited by 26 publications

References 43 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

T‐cell acute lymphoblastic leukaemia: recent molecular biology findings

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

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