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t(3;5)(q26;q31) H2AFY/MECOM

Written2018-11Jean Loup Huret

Abstract Review on t(3;5)(q26;q31) H2AFY/MECOM, with data on clinics, and the genes involved.

Keywords Chromosome 3; chromosome 5; H2AFY; MECOM; Acute myelomonocytic leukaemia

(Note : for Links provided by Atlas : click)


ICD-Topo C420,C421,C424
ICD-Morpho 9867/3 Acute myelomonocytic leukaemia
Atlas_Id 1837

Clinics and Pathology

Disease Acute myelomonocytic leukaemia (M4-AML)
Epidemiology Only one case to date, a 76-year-old male patient (Han et al., 2018).
Evolution He achieved complete remission (CR), but he relapsed and died 10 months after diagnosis.

Genes involved and Proteins

Gene NameMECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1-EVI1)
Location 3q26.2
Note MECOM is a nuclear transcription factor that plays an essential role in the proliferation and maintenance of hematopoietic stem cells and can inhibit myeloid differentiation. Two alternative forms exists, one generated from EVI1, the other MECOM (MDS1 and EVI1 complex locus) through intergenic splicing with MDS1 (myelodysplasia syndrome 1), a gene located 140 kb upstream of EVI1.
Protein The protein encoded by this gene is a transcriptional regulator involved in cell differentiation and proliferation, and apoptosis. The encoded protein can interact with transcriptional coactivators (KAT2B (P/CAF), CREBBP (CBP)) and corepressors (CTBP1, HDAC) as well as other transcription factors (GATA1, SMAD3) (de Braekeleer et al., 2012)
Gene NameH2AFY (H2A histone family member Y)
Location 5q31.1
Protein H2AFY codes for the proteins MACROH2A1. The first exon is non-coding. Due to alternative exons 6 (coding exons 5), coding for amino acids (aa) 198-226 or 229, there are 2 isoforms. Isoform MacroH2A1.1: 369 aa; 39,1 kDa; Isoform MacroH2A1.2: 372 aa, 39,6 kDa; This protein comprises a histone H2A domain (aa: 2-117; length: 116 aa) with a HA2 signature: AGVIFPV (aa: 19-25), a Lys-rich region (aa: 118-162; length: 45 aa) with a SQ-motif (aa 139-140) which can be phosphorylated by PIKKs, and a macro domain (aa: 184-370; length: 187). Ubiquitination sites are at Lys115, Lys116 and Lys119 (Ogawa et al., 2005). Glycines (Gly224 and Gly314) are required for PAR (poly(ADP-ribose)) binding.
MacroH2A1.1 is mainly found in differentiated, non-proliferative tissues, MacroH2A1.1 is upregulated in senescent cells; MacroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation (Sporn and Jung 2012).
MACROH2A1 regulates gene transcription, DNA damage response, mitochondrial respiration and senescence.
Methylations/acetylations MacroH2A1 is found on autosomes as part of facultative heterochromatin and is localized at two functionally distinct chromatin subtypes marked by trimethylation of histone H3 on lysine 27 (H3K27me3) or as part of transcriptionally active euchromatin marked by nine histone acetylations (H2B at K15 and K20; H3 at K4, K14 and K18; H4 at K91; and H2A at K5) where it can either positively or negatively regulate transcription (reviewed in Ruiz and Gamble 2018).
MacroH2A1.1-PARP1 axis Stressing signals generated during DNA damage repair, senescence, hormonal response, heat shock, or differentiation promote the binding of MacroH2A1.1 to activated PARP1 (poly(ADP-ribose) polymerase 1), creating the macroH2A1.1-PARP1 axis. MacroH2A1.1 recruit active PARP1 to chromatin and promotes the CREBBP -mediated acetylation of H2B K12 and K120, which either positively or negatively regulates the expression of MacroH2A1-target genes. On the other hand, when MacroH2A1.1 is highly expressed, MacroH2A1.1 can bind and inhibit PARP1 activity Chen et al., 2014; Hurtado-Bagès et al., 2018).
MacroH2A1 regulates mitochondrial respiration MacroH2A1.1 reduces nuclear NAD+ consumption through PARP1 inhibition, allowing maintenance of mitochondrial NAD+ pools that are critical for respiration (Posavec Marjanovic et al., 2014).
Epithelial-mesenchymal transition MacroH2A1.1 isoform, but not MacroH2A1.2, can suppress EMT induction.
Cancer Upregulation of mH2A1 induces SKP2 subsequent CDK8 downregulation contributes to growth defect, G2/M arrest, polyploidy and tumour suppression in breast cancer (Xu et al., 2015). MacroH2A1.2, one of the MacroH2A isoforms (see above), has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis and prostate cancer-induced osteoclastogenesis. Overexpression of mH2A1.2, but not mH2A1.1, in breast cancer cells significantly increased ERBB2 expression and tumorigenicity (Li et al., 2012). Re-expression of MacroH2A1.1 suppressed cancer cell proliferation, anchorage-independent growth and cell invasiveness in breast cancer, and suppressed metastasis of melanoma through regulation of CDK8. Loss of MacroH2A1.1 was associated with cell growth and metastasis and a worse outcome in colon cancer. Conversely, MacroH2A1.2 levels have been found to be similar in all tumors independently of proliferation (Sporn and Jung 2012). Patients with low MacroH2A1.1 levels in lung tumor samples recur more likely. MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells. In contrast, in the claudin-low subtype of triple negative breast cancer ( ESR1 -, PGR -, normal ERBB2) presenting a high MacroH2A1.1 mRNA ratio exhibit a poor outcome , through epithelial-mesenchymal transition process towards metastatic development (Lavigne et al., 2014).

Result of the chromosomal anomaly

Hybrid gene
Description 5'H2AFY-3'MECOM. The breakpoint in 5q31.1 was located in intron 5 of H2AFY, and the breakpoint in 3q26 was located in intron 1 of MECOM. H2AFY exon 5 was fused to MECOM exon 2 (Han et al., 2018).

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


Chen H, Ruiz PD, Novikov L, Casill AD, Park JW, Gamble MJ
1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation Nat Struct Mol Biol
PMID 25306110
H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia
Han Q, Lu J, Wang J, Ye J, Jiang X, Chen H, Liu C, Chen L, Lin T, Chen S, Sun M, Gao F
Cancer Genet 2018 Apr;222-223:9-12
PMID 29666008
The MacroH2A1
Hurtado-Bagès S, Guberovic I, Buschbeck M
1 - PARP1 Axis at the Intersection Between Stress Response and Metabolism Front Genet
PMID 30356649
Increased macroH2A1
Lavigne AC, Castells M, Mermet J, Kocanova S, Dalvai M, Bystricky K
1 expression correlates with poor survival of triple-negative breast cancer patients PLoS One
PMID 24911873
The atypical histone macroH2A1
Li X, Kuang J, Shen Y, Majer MM, Nelson CC, Parsawar K, Heichman KA, Kuwada SK
2 interacts with HER-2 protein in cancer cells J Biol Chem
PMID 22589551
Histone variant macroH2A1
Ogawa Y, Ono T, Wakata Y, Okawa K, Tagami H, Shibahara KI
2 is mono-ubiquitinated at its histone domain Biochem Biophys Res Commun
PMID 16129414
Posavec Marjanović M, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M
1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption Nat Struct Mol Biol
PMID 28991266
MacroH2A1 chromatin specification requires its docking domain and acetylation of H2B lysine 20
Ruiz PD, Gamble MJ
Nat Commun 2018 Dec 3;9(1):5143
PMID 30510186
Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer
Sporn JC, Jung B
Am J Pathol 2012 Jun;180(6):2516-26
PMID 22542848
Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis
Xu D, Li CF, Zhang X, Gong Z, Chan CH, Lee SW, Jin G, Rezaeian AH, Han F, Wang J, Yang WL, Feng ZZ, Chen W, Wu CY, Wang YJ, Chow LP, Zhu XF, Zeng YX, Lin HK
Nat Commun 2015 Mar 30;6:6641
PMID 25818643
de Braekeleer E, Douet-Guilbert, N, Le Bris MJ, Basink A, Morel F, de Braekeleer M.
Atlas Genet Cytogenet Oncol Haematol. 2013;17(7):491-493.


This paper should be referenced as such :
Jean-Loup Huret
t(3;5)(q26;q31) H2AFY/MECOM
Atlas Genet Cytogenet Oncol Haematol. 2019;23(10):310-311.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Translocations implicated (Data extracted from papers in the Atlas)

 t(3;5)(q26;q31) H2AFY/MECOM

External links

Mitelman databaset(3;5)(q26;q31)
arrayMap (UZH-SIB Zurich)Morph ( 9867/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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