ins(X;11)(q28;q23q23) KMT2A/FLNA
ins(11;X)(q23;q28q12) KMT2A/FLNA

2018-11-01   Elena Zerkalenkova , Yulia Olshanskaya , Tatiana Gindina 

1.R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russian Federation / e-mail: tatgindina@gmail.com (TG); Dmitry Rogachev Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Samora Mashela str., 1, Moscow, Russia (EZ, YuO), eazerkalenkova@gmail.com

Abstract

Ins(11;X)(q23;q28q12) and ins(X;11)(q28;q23q23) are found so far in acute myelomonocytic leukaemia and carries a poor prognosis. The genes implicated in this disease are KMT2A and FLNA.

Clinics and Pathology

Disease

Acute myelomonocytic leukaemia (FAB-M4)

Phenotype stem cell origin

Poorly defined, only three cases described to date, see Table 1 (De Braekeleer et al., 2009; Matveeva et al., 2015; Lentes et al., 2016).
Table 1. General characteristics and treatment course of patients with KMT2A/FLNA
RefAge/sexWBC (x109/L) CNSDiagnosisSurvivalKaryotypeKMT2A/FLNA
15 mo/M22yesM4-AML2 mthsins(11;X)(q23;q28q12)Intron 9 / exon 16
27 mo/M81noM4-AML3 mths+6,ins(X;11)(q28;q23q23)Intron 10 / intron 19
313 mo/M108UnknownM4-AML1 mthdel(X)(q12),+del(X)(q12),+8,ins(11;X)(q23;q28q12),+19Exon 11 / exon 11

CNS: CNS involvement; M4-AML: Acute myelomonocytic leukaemia; KMT2A/FLNA breakpoints
Reference: (1) De Braekeleer et al., 2009; (2) Matveeva et al., 2015; (3) Lentes et al., 2017.

Epidemiology

All 3 patients were boys, aged 5 to 13 months.

Cytology

Bone marrow aspirates demonstrated hypercellularity, blasts show typical AML-M4 features - high basophilic cytoplasm without Auer rods, moderate to high nucleocytoplasmic ratio.

Cytogenetics

ins(11;X)(q23;q28q12) or ins(X;11)(q28;q23q23) with KMT2A rearrangement.

Genes

KMT2A at 11q23, FLNA at Xq28

Prognosis

Poor prognosis (see Table 1): all described patients died either from the disease progression (De Braekeleer et al., 2009; Matveeva et al., 2015) or from multiple organ failure (Lentes et al., 2016). In one patient, there was no remission; and he died 2 months after diagnosis of disease progression. In the second case, a complete remission (CR) was obtained; there was two relapses; a bone marrow transplantation (BMT) 8 months after diagnosis from MUD, but the patient died on day +100 after BMT of disease progression. In the third case, there was a CR; but the patient died 38 days after diagnosis of multiple organ failure.

Cytogenetics

Cytogenetics morphological

ins(X;11)(q28;q23q23) is cryptic
Atlas Image
(A) - the probe hybridized to interphase nuclei displayed two normal KMT2A copies and one additional copy of 5-KMT2A. (B) - when hybridized to metaphase, the probe displayed the additional copy of KMT2A 5-portion translocated to chromosome X (Matveeva et al., 2015).

Probes

MLL dual color break apart rearrangement probe

Additional anomalies

Sole abnormality in one case, accompanied with trisomy 6 in one case, and disomy X, deletion del(X)(q12), trisomy 8 and trisomy 19 (complex karyotype) in the third case.

Genes Involved and Proteins

Gene name
KMT2A (lysine methyltransferase 2A)
Location
11q23.3
Dna rna description
KMT2A gene consists of 37 exons encoding a 3969 amino-acid nuclear protein with a molecular weight of nearly 431 kDa.
Protein description
431 kDa; contains two DNA binding motifs (a AT hook and Zinc fingers), and a DNA methyl transferase motif; wide expression; nuclear localization. KMT2A gene encodes a transcriptional coactivator that plays an crucial role in regulating gene expression during early development and hematopoiesis.
Gene name
FLNA (filamin A)
Location
Xq28
Dna rna description
FLNA gene consists of 48 exons encoding a 2647 amino-acid protein with a molecular weight of 280739 Da.
Protein description
280739 Da; belongs to the filamins family of high molecular mass structural proteins; contains N-terminal actin-binding domain; widely expressed; found in cytoplasm and cell cortex; involved into cell trafficking and actin cytoskeleton organization (Kim et al., 2011). Filamin A is an actin crosslinking phosphoprotein of the peripheral cytoplasm and interacts with Pho proteins. FLNA is crucial in many processes involving cytoskeletal reorganization (e.g. proliferation, differentiation, and apoptosis). It plays an important role in mitotic spindle function and is required for the G2/M cell cycle (Lentes et al., 2016).
Germinal mutations
Germline FLNA missense mutations are associated with otopalatodigital syndrome (OPD) spectrum of skeletal disorders. OPD is X-linked dominant and lethal in male patients. These mutations lead to a gain-of-function of filamin A (Clark et al., 2009). On the other hand, loss-of-function FLNA mutations manifest as disorders of neuronal migration, also leading to early prenatal death in male patients (Kasper et al., 2013).

Result of the Chromosomal Anomaly

Atlas Image
Upper line: KMT2A/FLNA fusion gene sequence and KMT2A/FLNA fusion transcript RT-PCR. Lower line: KMT2A/FLNA fusion transcript Sanger sequencing, note the intron retention event (Matveeva et al., 2015).

Description

KMT2A/FLNA fusion gene contains 5-portion of KMT2A and 3-portion of FLNA. Breakpoints are various in both genes (Table 1). In the first case, the KMT2A/FLNA fusion showed a breakpoint in intron 10 of KMT2A and intron 19 of FLNA resulting in an in-frame fused mRNA (De Braekeleer et al., 2009). In the second one, an additional copy of 5 KMT2A inserted into the long arm of the X chromosome resulting in an in-frame KMT2A/FLNA fusion gene with breakpoints in intron 9 of KMT2A and exon 16 of FLNA (Matveeva et al., 2015). And, in the third case, the breakpoint junction was localized in exon 11 of KMT2A and exon 11 of FLNA. However, a potentially functional transcript was generated by alternative splicing, where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 117 (Lentes et al., 2016).

Transcript

KMT2A/FLNA fusion transcripts were detected by RT-PCR in all cases (De Braekeleer et al., 2009; Matveeva et al., 2015; Lentes et al., 2016). It is notable that in two cases DNA junction was out-of-frame; nevertheless, functional transcripts were produced by alternative splicing (see above) either by intron retention (Matveeva et al., 2015) or by using a new splice acceptor site (Lentes et al., 2016).

Detection protocole

KMT2A/FLNA fusion genes were detected by LDI-PCR (De Braekeleer et al., 2009; Matveeva et al., 2015; Lentes et al., 2016).

Oncogenesis

Probably, the fusion KMTA/FLNA has an oncogenic potential by functioning as gain-of-function mutants of KMT2A causing an upstream constitutive activation that promotes myeloid transformation and leads to AML. In all publications, due to lack of material, the existence of a functional protein has not been proven (Lentes, 2017).

Bibliography

Pubmed IDLast YearTitleAuthors
197733412009Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.Clark AR et al
196220922009FLNA, a new partner gene fused to MLL in a patient with acute myelomonoblastic leukaemia.De Braekeleer E et al
236369022013Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.Kasper BS et al
210951892011Filamin A mediates interactions between cytoskeletal proteins that control cell adhesion.Kim H et al
282534922016Identification of a Cryptic Insertion ins(11;X)(q23;q28q12) Resulting in a KMT2A-FLNA Fusion in a 13-Month-Old Child with Acute Myelomonocytic Leukemia.Lentes J et al
258921232015A new variant of KMT2A(MLL)-FLNA fusion transcript in acute myeloid leukemia with ins(X;11)(q28;q23q23).Matveeva E et al

Summary

Fusion gene

KMT2A/FLNA

Note

The ins(X;11)(q28;q23q23) rearrangement is a form of ins(11;X)(q23;q28q12). The two chromosome anomalies are variants of each other, they lead to the formation of the same fusion gene KMT2A/FLNA.

Citation

Elena Zerkalenkova ; Yulia Olshanskaya ; Tatiana Gindina

ins(X;11)(q28;q23q23) KMT2A/FLNA
ins(11;X)(q23;q28q12) KMT2A/FLNA

Atlas Genet Cytogenet Oncol Haematol. 2018-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1804/ins(11;x)(q23;q28q12)

External Links