- Short communication
- Open Access
Transcriptome sequencing reveals CHD1 as a novel fusion partner of RUNX1 in acute myeloid leukemia with t(5;21)(q21;q22)
© Yao et al. 2015
- Received: 9 August 2014
- Accepted: 25 March 2015
- Published: 11 April 2015
RUNX1/AML1, which is a Runt family transcription factor critical for normal hematopoiesis, is frequently mutated or translocated in a broad spectrum of hematopoietic malignancies.
We describe here the case of a 54-year-old female developed acute myeloid leukemia with a t(5;21)(q21;q22). Transcriptome sequencing identified the chromodomain-helicase-DNA-binding protein 1 gene, CHD1, as a novel partner gene of RUNX1. Furthermore, the patient was found to harbor FLT3-ITD mutation, which might collaborated with CHD1-RUNX1 in the development of acute myeloid leukemia.
We have identified CHD1 as the RUNX1 fusion partner in acute myeloid leukemia with t(5;21)(q21;q22).
- Fusion gene
- Acute myeloid leukemia
The RUNX1 (previously AML1) gene encodes a DNA binding subunit of the core binding factor (CBF), which is critical for normal hematopoiesis. It is reported that RUNX1 frequently mutated or translocated with at least 61 different chromosomal loci in a broad spectrum of hematopoietic malignancies. To date, more than 20 distinct RUNX1 gene fusions have been reported in a variety of hematologic malignancies [1-4]. However, about half of RUNX1 translocations remain uncharacterized at the molecular level. Identification of those unknown fusion partners of RUNX1 will provide more clues about the molecular and pathogenic mechanisms of these translocations. Recently, whole transcriptome sequencing (also known as RNA-Sequencing, RNA-seq) has been shown as an efficient tool to identify uncharacterized fusion genes . We describe here the identification of a novel fusion gene involving RUNX1 by case of a 54-year-old female developed acute myeloid leukemia with a t(5;21)(q21;q22) by transcriptome sequencing.
A 54-year-old female was admitted to our hospital in January 2011 because of fever and fatigue. Examination of peripheral blood indicated a platelet count of 103 × 109/L, hemoglobin level of 60 g/L, and a white blood cell count of 9.37 × 109/L with 22% circulating blasts. Bone marrow (BM) was hypercellular with 87.5%. Flow cytometry (FCM) immunophenotyping analysis showed positivity for CD34, CD14, CD13, CD33, CD117, CD15, CD11b and HLA-DR, as well as negativity for CD19, CD10, CD22, CD20, CD7, CD2, CD5 and CD3. The patient’s clinical picture was consistent with a diagnosis of AML-M4 according to the FAB classification, and AML not otherwise specified, acute myelomonocytic leukemia according to the World Health Organization (WHO) classification . She was treated with induction chemotherapy of the IA regimen, including idarubicin and cytosine arabinoside. She achieved complete remission (CR) and received several courses of consolidation chemotherapy. However, her leukemia relapsed in April 2012. She was refractory to several courses of intensive combination chemotherapy and died in April 2013.
Internal tandem duplication (ITD) mutations of the FLT3 gene have been described in approximate 20-25% of AML . In the present case, we identified an internal tandem mutation of the FLT3 gene (FLT3-ITD) by using Gene Scanning as previously described  (Additional file 1: Figure S1).
Most chimeric gene involving RUNX1 fuse the 5’ part of the RUNX1 gene with the 3’ part of the partner gene. These fusion proteins retain RHD domain of RUNX1 which is responsible for heterodimerization with the core-binding factor-β (CBF-β) and DNA binding, but loss the TAD and TID domains, such as RUNX1-RUNXT1, RUNX1-MECOM, and RUNX1-LPXN . However, there are two chimeric genes, namely ETV6-RUNX1 and USP16-RUNX1, which fuse the 5’ region of partner gene with 3’ region of RUNX1. ETV6-RUNX1 retains RHD, TAD and TID domains of RUNX1. However, USP16-RUNX1 does not retain the RHD and no putative chimeric protein seems to be encoded due to loss of the open-reading frame [10,11]. Notably, our study identify a novel fusion gene CHD1-RUNX1, which is generated by 5’ region of CHD1 and 3’ region of RUNX1, retains the whole TAD and TID, and part of RHD. The incomplete RHD is likely to impair the DNA binding capacity of RUNX1 or its heterodimerization with CBF-β.
CHD1 locates in 5q15 and encodes a protein composed of 1710 amino acids. CHD1 is a chromatin-remodeling enzyme that belongs to the chromodomain family of proteins that play an important role in transcriptional regulation and developmental processes . It has been reported that CHD1 is involved in assembly, shifting and removal of nucleosomes from the DNA double helix to keep them in an open and transcriptionally active state . Two research groups have reported independently that CHD1 plays a tumor-suppressor role in prostate cancer [14,15]. However, the role of CHD1 in hematological malignancies remains unknown. By analyzing karyotypic results of over 6000 newly-diagnosed patients with acute leukemia admitted to our institute between January 1985 and February 2015, we detected t(5;21)(q21;q22) translocation in two AML patients. One was a 47-year-old male patient who was diagnosed with AML-M2 in April 1994. The other one (the present case, NO. 201100834) was a 54-year-old female diagnosed with AML-M4. We identified the CHD1-RUNX1 fusion transcript from the female case.
Animal models have revealed that RUNX1-related translocations or haploinsufficiency of RUNX1 are necessary but not sufficient for leukemogenesis [16,17], which suggests the requirement for additional genetic lesion for the development of leukemia. Internal tandem duplications (ITDs) in the juxtamembrane (JM) domain of FLT3 that lead to constitutive kinase activation in AML are associated with higher early relapse rate and inferior overall survival in patients with normal karyotype [18-20]. Furthermore, FLT3-ITD could cooperate strongly in leukemia induction with a variety of leukemia-initiating gene fusions such as AML1-ETO, MLL-AF9, or PML-RAR α [17,21,22]. We found the present patient harboring the FLT3-ITD mutation which might cooperate with CHD1-RUNX1 in the induction of AML.
Taken together, we have identified a novel CHD1-RUNX1 fusion consistent with the described t(5;21)(q21;q22) in a female patient with de novo AML (M4). Its role in the pathogenesis of AML still requires extensive investigation.
This work was supported by grants from National Key Scientific Projects of China (2011CB933501), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Foundation of China (81070416), Jiangsu Provincial Special Program of Medical Science (BL2012005), Jiangsu Province’s Key Medical Center (ZX201102), and Jiangsu Province Natural Science Fund for Distinguished Young Scholars (BK2012006).
- Ito Y. RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res. 2008;99:33–76.PubMedView ArticleGoogle Scholar
- Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.View ArticleGoogle Scholar
- Abe A, Katsumi A, Kobayashi M, Okamoto A, Tokuda M, Kanie T, et al. A novel RUNX1-C11orf41 fusion gene in a case of acute myeloid leukemia with a t(11;21)(p14;q22). Cancer Genet. 2012;205:608–11.PubMedView ArticleGoogle Scholar
- Giguère A, Hébert J. Identification of a novel fusion gene involving RUNX1 and the antisense strand of SV2B in a BCR-ABL1-positive acute leukemia. Genes Chromosomes Cancer. 2013;52(12):1114–22.PubMedView ArticleGoogle Scholar
- Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X, et al. Transcriptome sequencing to detect gene fusions in cancer. Nature. 2009;458:97–101.PubMed CentralPubMedView ArticleGoogle Scholar
- Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.Google Scholar
- Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116:5089–102.PubMedView ArticleGoogle Scholar
- Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–80.PubMedGoogle Scholar
- De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Ferec C, De Braekeleer M. RUNX1 translocations and fusion genes in malignant hemopathies. Future Oncol. 2011;7:77–91.PubMedView ArticleGoogle Scholar
- Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffe M, Jonveaux P, et al. High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood. 1995;86:4263–9.PubMedGoogle Scholar
- Gelsi-Boyer V, Trouplin V, Adélaïde J, Aceto N, Remy V, Pinson S, et al. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer. 2008;8:299.PubMed CentralPubMedView ArticleGoogle Scholar
- Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS. Characterization of the CHD family of proteins. Proc Natl Acad Sci U S A. 1997;94:11472–7.PubMed CentralPubMedView ArticleGoogle Scholar
- Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason MJ, Heidersbach A, et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature. 2009;460:863–8.PubMed CentralPubMedGoogle Scholar
- Liu W, Lindberg J, Sui G, Luo J, Egevad L, Li T, et al. Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene. 2012;31:3939–48.PubMed CentralPubMedView ArticleGoogle Scholar
- Huang S, Gulzar ZG, Salari K, Lapointe J, Brooks JD, Pollack JR. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene. 2012;31:4164–70.PubMedView ArticleGoogle Scholar
- Van der Weyden L, Giotopoulos G, Rust AG, Matheson LS, van Delft FW, Kong J, et al. Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice. Blood. 2011;118:1041–51.PubMed CentralPubMedView ArticleGoogle Scholar
- Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest. 2005;115:2159–68.PubMed CentralPubMedView ArticleGoogle Scholar
- Nazha A, Cortes J, Faderl S, Pierce S, Daver N, Kadia T, et al. Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia. Haematologica. 2012;97:1242–5.PubMed CentralPubMedView ArticleGoogle Scholar
- Walker A, Marcucci G. Impact of molecular prognostic factors in cytogenetically normal acute myeloid leukemia at diagnosis and relapse. Haematologica. 2011;96:640–3.PubMed CentralPubMedView ArticleGoogle Scholar
- Whitman SP, Maharry K, Radmacher MD, Becker H, Mrózek K, Margeson D, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloidleukemia: a Cancer and Leukemia Group Bstudy. Blood. 2010;116:3622–6.PubMed CentralPubMedView ArticleGoogle Scholar
- Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia. 2008;22:66–77.PubMed CentralPubMedView ArticleGoogle Scholar
- Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A. 2002;99:8283–8.PubMed CentralPubMedView ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.