| Disease |
Acute myelomonocytic leukaemia (FAB-M4) |
| Phenotype / cell stem 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
| Ref | Age/sex | WBC (x109/L) | CNS | Diagnosis | Survival | Karyotype | KMT2A/FLNA | | 1 | 5 mo/M | 22 | yes | M4-AML | 2 mths | ins(11;X)(q23;q28q12) | Intron 9 / exon 16 | | 2 | 7 mo/M | 81 | no | M4-AML | 3 mths | +6,ins(X;11)(q28;q23q23) | Intron 10 / intron 19 | | 3 | 13 mo/M | 108 | Unknown | M4-AML | 1 mth | del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23;q28q12),+19 | Exon 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 Morphological | ins(X;11)(q28;q23q23) is cryptic |
| |  |
| |
| |
(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. |
| Gene Name | FLNA (filamin A) |
| Location | Xq28 |
| Dna / Rna | FLNA gene consists of 48 exons encoding a 2647 amino-acid protein with a molecular weight of 280739 Da. |
| Protein | 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). |
Hybrid gene| |
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 | KMT2A/FLNA fusion genes were detected by LDI-PCR (De Braekeleer et al., 2009; Matveeva et al., 2015; Lentes et al., 2016). |
| | |
| Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders |
| Clark AR, Sawyer GM, Robertson SP, Sutherland-Smith AJ |
| Hum Mol Genet 2009 Dec 15;18(24):4791-800 |
| PMID 19773341 |
| |
| FLNA, a new partner gene fused to MLL in a patient with acute myelomonoblastic leukaemia |
| De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Meyer C, Marschalek R, Férec C, De Braekeleer M |
| Br J Haematol 2009 Sep;146(6):693-5 |
| PMID 19622092 |
| |
| Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia |
| Kasper BS, Kurzbuch K, Chang BS, Pauli E, Hamer HM, Winkler J, Hehr U |
| Am J Med Genet A 2013 Jun;161A(6):1323-8 |
| PMID 23636902 |
| |
| Filamin A mediates interactions between cytoskeletal proteins that control cell adhesion |
| Kim H, McCulloch CA |
| FEBS Lett 2011 Jan 3;585(1):18-22 |
| PMID 21095189 |
| |
| Identification 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, Thomay K, Schneider DT, Bernbeck B, Reinhardt D, Marschalek R, Meyer C, Schlegelberger B, Göhring G |
| Cytogenet Genome Res 2016;150(3-4):281-286 |
| PMID 28253492 |
| |
| A new variant of KMT2A(MLL)-FLNA fusion transcript in acute myeloid leukemia with ins(X;11)(q28;q23q23) |
| Matveeva E, Kazakova A, Olshanskaya Y, Tsaur G, Shelikhova L, Meyer C, Marschalek R, Novichkova G, Maschan M, Maschan A |
| Cancer Genet 2015 Apr;208(4):148-51 |
| PMID 25892123 |
| |
