Acute myelomonocytic leukaemia (FAB-M4)

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.

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

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

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

KMT2A at 11q23, FLNA at Xq28

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.

ins(X;11)(q28;q23q23) is cryptic

MLL dual color break apart rearrangement probe

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.

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).

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).

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

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).

KMT2A/FLNA

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.