a rare cause of MECOM overexpression in acute myeloid leukemia.
Index of Case Report: Volume 1: Issue 1
1. Karolien Beel, MD, PhD, Centre of Human Genetics, University Hospitals Leuven, Belgium
2. Inge Vrelust, MD, dept. of Hematology, AZ Turnhout, Turnout, Belgium
3. Barbara Dewaele, Ir, PhD, Centre of Human Genetics, University Hospitals Leuven , Belgium
4. Lucienne Michaux, MD, PhD, Centre of Human Genetics, University Hospitals Leuven, and KULeuven, Leuven, Belgium
Increased expression of MECOM is found in approximately 10% of patients with acute myeloid leukemia (AML) and is associated with chemoresistance and a poor prognosis. Chromosomal translocations involving chromosome band 3q26.2 explain only a minority of cases with MECOM overexpression. Here, we present a patient with intrachromosomal MECOM amplification on a ring chromosome, demonstrating the complexity of mechanisms leading to MECOM overexpression in AML.
Our case underscores the need for FISH for the characterisation of chromosome 3 aberrations in AML. It also illustrates that overexpression of MECOM, irrespective of the underlying mechanism, is often accompanied by additional (secondary) karyotypic changes.
EVI1/MECOM is known as one of the most aggressive oncogenes since its discovery in 1988. Increased expression of the EVI1 (ecotropic virus integration site 1) gene is found in approximately 10% of patients with acute myeloid leukemia (AML) and is associated with chemoresistance and a poor prognosis. EVI1 is a splice form of MECOM (MDS1 and EVI1 complex locus protein EVI1), a recently introduced gene name in nomenclature. The gene promotes cell proliferation, impairs cell differentiation and inhibits apoptosis, as induced by antileukemic drugs1.
Increased expression of MECOM can be caused by chromosomal translocations involving the MECOM locus at band 3q26.2. At least 12 recurrent chromosomal rearrangements involving MECOM have been described, accounting for 2% of AML cases, of which rearrangement of MECOM with RPN1 [inv(3)(q21q26), t(3;3)(q21;q26)], ETV6 [t(3;12)(q26;p13)] and RUNX1 [t(3;21)(q26;q22)] are the most common2. In these cases, overexpression of MECOM results from the juxtaposition of a strong enhancing region next to the MECOM coding sequence. Some translocations can be detected with conventional chromosomal banding, but complex or cryptic rearrangements require FISH for identification. In addition, MECOM overexpression can be observed without a detectable 3q26 chromosomal rearrangement (between 6 and 11% of patients with AML)4. Extrachromosomal amplification of MECOM on double minutes has been described in rare cases3. Epigenetic changes affecting MECOM have also been suggested.
Here, we report a case with MECOM overexpression on a ring chromosome. This male patient was diagnosed with acute megakaryoblastic leukemia (FAB AML M7) at the age of 73y. His history consisted of coronary artery disease and systemic lupus erythematosus, for which steroids and cyclophosphamide had been briefly administered in the past. At the time of diagnosis, he was mildly cognitively impaired and showed signs of malnutrition. Five months earlier, he had suffered from a cerebellar infarction and had been resuscitated. He came to the Hematology department with a progressive pancytopenia with 2% peripheral blasts. Bone marrow aspirate showed acute megakaryoblastic myeloid leukemia with 30,6% blasts with the following phenotype: CD34+, CD13+, CD33+, CD117 +/-, CD36+, HLADR negative to weakly+, CD71 weakly+, CD105 weakly+, CD35 weakly +, CD10-, CD16-, cytCD79a-, cytCD3-, CD3-, cytMPO-, CD14-, CD15-, CD64-, CD11b partially+. He was treated with decitabine for one cycle and died at home, within one month after diagnosis.
The bone marrow karyotype (see figure 1 and formula below) was extremely complex, and included e.g. additional material on one chromosome 3 [add3] and monosomy 5. FISH analysis using Abbott Molecular Laboratories (Chicago, IL USA) and Metasystems (Altluβheim, Germany) probes was subsequently performed. Using a dual colour fusion MECOM/RPN1 probe, one normal chromosome 3 and one ring chromosome, displaying amplification of MECOM were observed in 43% of interphase nuclei and 2/5 metaphases (see figure 2). Additionally, a marker with 1 MECOM signal without RPN1 was seen, and the add(3) displayed neither MECOM nor RPN1. Using a whole chromosome paint, no other material derived from chromosome 3 was detected on the marker chromosome, whereas part of the add(3) and almost all the ring were painted. In addition, using a centromeric probe for chromosome 3, no signal was observed on the ring.
Our case illustrates a rare and rather complex presentation of intrachromosomal MECOM overexpression and supports the finding that overexpression of MECOM, irrespective of the underlying mechanism, is often accompanied by additional karyotypic changes, such as deletions of chromosome 5q.
- Lugthart,,S., van Drunen, E., van Norden, Y., van Hoven, A., Erpelinck, C.A. , Valk, P.J. , Beverloo, H.B. , Lowenberg, B., Delwel, R. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood. 2008;111:4329-4337.
- Hinai, A.A., Valk, P.J. Aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol. 2016; 172(6):870-878.
- Volkert, S., Schnittger, S., Zenger, M. Kern, W., Haferlach, T., Haferlach, C. Amplification of EVI1 on cytogenetically cryptic double minutes as new mechanism for increased expression of EVI1. Cancer Genet. 2014; 207(3):103-108.
- Wieser, R. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene. 2007; 396(2):346-357.
Figure 1. Representative R-banded metaphase showing a complex karyotype including -5:
39~49,XY, der(3)t(3;?)(q11;?),-5,+6,+8,-9,der(11)t(9;11)(p13;p12),-13,-19,-21,add(21)(q21),+ der(?)t(19;?) ,+r,+mar[cp7]/46,XY
A B C
A= 63159644.068 with Vysis RPN1/MECOM DF FISH Probe Kit (CE) (RPN1/3q21.3 SpectrumGreen, MECOM/3q26.2 SpectrumOrange)
B= 63159644.088 with Metasystems XCP 3 Orange (painting of chromosome 3)
C= 63159644.106 with Metasystems XCP 19 Orange (painting of chromosome 19) and XCE 3 Green (centromere 3)
Full arrow = ring
Arrow with line = mar2
Empty arrow = normal chromosome 3
Empty triangle = der(3)t(3;?)(q11;?)
Full triangle = der(?)t(19;?)
Review Status: Pending