HAEM5:Acute myeloid leukaemia with MECOM rearrangement

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);GATA2, MECOM.

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Primary Author(s)*

Gordana Raca MD PhD, University of Southern California, Los Angeles

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia with MECOM rearrangement

Definition / Description of Disease

The inv(3)(q21q26.2)/t(3;3)(q21;q26.2) defines a distinctive cytogenetic subtype of acute myeloid leukemia (AML) in 2008 WHO classification (AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2), although it is currently not recognized as an abnormality pathognomonic for diagnosis of AML irrespective of blast percentage. This abnormality also occurs in myelodysplastic syndrome (MDS), where it is associated with aggressive course and a high risk of progression to AML. It can also rarely be found in other myeloid neoplasms, including chronic myelogenous leukemia (mostly during accelerated phase or in blast crisis), other myeloproliferative neoplasms (MPN), and in overlap MDS/MPNs including chronic myelomonocytic leukemia.

inv(3)(q21q26.2) and t(3;3)(q21;q26.2) are variant rearrangements with similar consequences at the molecular level and similar disease associations and clinical implications.

In addition to the balanced inversion and translocation involving the bands 3q21 and 3q26.2, other 3q abnormalities are also common in AML. A study of 6515 adults with newly diagnosed AML detected 3q abnormalities in 4.4% of the patients, and classified them in four categories:

1. t(3;3)/inv(3)
2. Translocations involving only the band 3q26.2
3. Translocations involving only the band 3q21
4. Other 3q abnormalities.

Further studies are needed to determine how the molecular pathogenesis and clinical features of AML with other 3q rearrangements compare with the AML with inv(3)/t(3;3).

Synonyms / Terminology

AML with RPN1-MECOM

Epidemiology / Prevalence

AML with inv(3)(q21q26.2) and t(3;3)(q21;q26.2) comprises 1-2.5% of all AML cases and less than 1% of all MDS cases.

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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The patients often present with anemia and normal or increased platelet counts. However, decreased platelet counts and hepatosplenomegaly can also be observed.

Sites of Involvement

Bone Marrow.

Morphologic Features

Common morphologic features include multilineage dysplasia, with atypical megakaryocytes (ie, small mono- or bilobed forms) and variable fibrosis. The most consistent bone marrow finding in this disorder is an increase in the number of megakaryocytes, many of which are morphologically abnormal. In some patients, almost all of the identifiable megakaryocytes are micromegakaryocytes.

Immunophenotype

Immunophenotypic studies typically show expression of CD13, CD33, HLA-DR, CD17(KIT) CD34 and CD38, occasionally with aberrant expression of CD7 and megakaryocytic markers like CD41 and CD61.

Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Diagnostic: The presence of inv(3)/t(3;3) defines a cytogenetic subtype of AML, however in the current WHO 2017 classification does not allow to make a diagnosis of AML if blast percentage <20%. Very poor prognosis and rapid progression of MDS with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) resulted in a proposal to consider neoplasms with these rearrangements as an AML with recurrent genetic abnormalities, irrespective of blast percentage.

BCR-ABL1 positive patients with CML and concomitant MECOM rearrangement are considered in an aggressive phase of CML (Accelerated Phase) rather than de novo AML with inv(3)/t(3;3)

Prognostic: The inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is associated with a dismal prognosis in both AML and MDS. Review of 6515 adult patients with newly diagnosed AML enrolled in prospective European trials showed 5-year OS of only 5.7% +/- 3 for AML with inv(3)/t(3;3), with the median survival os 10.3 months. This adverse prognostic impact of inv(3)/t(3;3) appears to be further enhanced by additional monosomy 7 and/or complex karyotype. Similarly, the prognosis of MDS with inv(3)/t(3;3) is also poor, and the revised International Prognostic Scoring System (IPSS-R) for MDS includes inv(3)/t(3;3) among its poor risk cytogenetic abnormalities.

Therapeutic: AML with inv(3)(q21q26.2) or t(3;3) (q21;q26.2) is an aggressive disease with short survival, in need for novel and more efficient treatments. Some studies have shown that arsenic trioxide induces targeted specific degradation of the AML1/MDS1/EVI1 oncoprotein, and an isolated case report described good response to Arsenic trioxide and thalidomide combination in a patient with MDS with inv(3).

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Monosomy 7 is the most common associated (secondary) cytogenetic abnormality (in ~66% of cases), and appears to further contribute to the adverse prognosis of the inv(3q)/t(3;3) abnormality. Complex karyotypes Deletion 5q

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Secondary mutations are found in all AML cases with inv(3) ot t(3;3). Mutations in genes activating RAS/TK signaling pathway are the most common mutation. NRAS (~30%), PTPN11(11%), FLT3 (13%) and KRAS (11%), as well as GATA2 (15%) , RUNX1 (12%) and NF1 (9%) , CBL (7%) , KIT (2%). CBL mutation is found often with concomitant GATA2 mutation.

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	GATA2, CBL
Secondary Mutations
Mutually Exclusive

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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The MECOM (MDS1 and EVI1 complex locus) gene in 3q26.3 is the key gene implicated in pathogenesis of AML with inv(3)/t(3;3). MECOM codes for several differentially spliced transcripts: MDS1-EVI1, MDS1 and EVI1. It consequently yields the MDS1-EVI1 [1239 amino acids (AA)], MDS1 (188AA) and EVI1 (1051AA) protein isoforms. While EVI1 deregulated expression has been reported to be critical in stem cell self-renewal and leukaemogenesis, the roles of MDS1 and MDS1-EVI1 in haematological malignancies remain unclear.

EVI1 is a zinc-finger nuclear transcription factor involved in many signaling pathways. It binds DNA through specific conserved sequences, interacts with a number of transcriptional and epigenetic regulators (CREBBP, CTBP, HDAC, KAT2B (P/CAF), SMAD3, GATA1, GATA2, DNMT3A, and DNMT3B), and mediates chromatin modifications and DNA hypermethylation. EVI1 plays a role in embryogenesis and its deficiency in mice is an embryonic lethal mutation. Among the many other observed defects, EVI1-/- mouse embryos have been shown to have defects in both the development and proliferation of hematopoietic stem cells (HSCs). It appears that depending on its binding partners, EVI1 can act as a transcriptional activator to promote the proliferation of hematopoietic stem cells (eg, when bound to GATA2) or as a transcriptional repressor inhibiting erythroid differentiation (eg, when bound to GATA1).

Changes at mRNA level: EVI1 proto-oncogene has early on been identified as aberrantly upregulated in almost all AML cases with inv(3) and t(3;3). Aberrant EVI1 expression is also found in a majority of AML patients with other 3q26 abnormalities and even in patients with myeloid leukemia and a normal karyotype, suggesting that inappropriate activation of this gene occurs through various mechanisms, but invariably confers an adverse prognosis. Interestingly, the breakpoints in chromosomal rearrangements that lead to EVI1 activation in AML with inv(3)/t(3;3) were shown to occur either 5' of the gene in the t(3;3) or 3' of the gene in the inv(3). It has long been thought that activation of EVI1 in malignant hematopoietic cells occurs by juxtaposition of the gene to enhancer elements of the housekeeping ribophorin gene located at 3q21. However, several groups have recently described a novel molecular mechanism by which the inv(3)/t(3;3) re-positions a distal GATA2 enhancer to activate MECOM expression, and simultaneously confer GATA2 functional haploinsufficiency. This mechanism presents a new paradigm for the pathogenesis of MDS/AML.

Changes at protein level: The inv(3)(q21q26.2)/t(3;3)(q21;q26.2) results in upregulation of the MECOM gene and increased levels of the EVI1 protein, but does not produce abnormal gene and protein fusions.

Key cellular pathways: EVI1 has been shown to be involved in multiple downstream signaling pathways, including the transforming growth factor beta (TGF-β) signaling (where EVI1 prevents transcription of the TGF-β induced anti-growth genes ) and c-Jun N-terminal kinase (JNK) signaling (where EVI1 prevents phosphorylation and activation of key transcription factors for the apoptotic response).

Genetic Diagnostic Testing Methods

1. Karyotype: Inv(3) and t(3;3) can typically be detected by routine karyotype analysis, although the inversion may be challenging to identify in the cases with poor morphology.
2. FISH: EVI1 break-apart FISH probe is commercially available and FISH testing is offered clinically by most clinical cytogenetic laboratories.

Familial Forms

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Additional Information

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Links

GATA2

MECOM

Up To Date Cytogenetics in AML

HNGC MECOM

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

Edited by: Fabiola Quintero-Rivera 8/3/2018

*Citation of this Page: “Acute myeloid leukaemia with MECOM rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_MECOM_rearrangement.