Acute megakaryoblastic leukemia (AMKL)

Acute megakaryoblastic leukemia (AMKL) was so far divided into three subgroups: AMKL arising in patients with Down syndrome (DS-AMKL), AMKL with a t(1;22)(p13;q13) giving rise of a 5 OTT - 3 MAL fusion gene, and "other" AMLKs, i.e. non Down syndrome / non t(1;22).
Two new categories have recently been individualized from the subgroup "non Down syndrome / non t(1;22)": the inv(16)(p13q24) CBFA2T3/GLIS2, and the t(11;12)(p15;p13) NUP98/KDM5A (Gruber et al., 2012; Thiollier et al., 2012).

Fourteen patients with data on sex and age are available; median age at diagnosis was 1 year - 1 year 4 months (range 6 months - 4 years 7 months).
The inv(16)(p13q24) CBFA2T3/GLIS2 was found in about 30% of non-Down syndrome pediatric AMKL cases (in 13 of 48 cases in Gruber et al., 2012, and 7 of 22 cases in Thiollier et al., 2012. So far, none of the 36 adult AMKL cases under study contained the chimeric transcript.
One patient had a Down syndrome (case SJAMLM7018 in Gruber et al., 2012), which shows that DS-AMKL and inv(16)-AMLK categories are not mutually exclusive.

Subgroup of patients with a significantly worse overall survival at 5 years as compared to patients with AMKL that lacked this chimeric transcript (28% versus 42% in Gruber et al., 2012); fusion associated with treatment-refractory disease (Thiollier et al., 2012).

5 CBFA2T3 - 3 GLIS2. Fusion between exon 10 of CBFA2T3 and exon 3 of GLIS2 in 6 cases (Gruber et al., 2012); fusion between exon 11 of CBFA2T3 and exon 3 of GLIS2 in 1 case (Thiollier et al., 2012); fusion between exon 11 of CBFA2T3 and exon 1 of GLIS2 in 1 case (Gruber et al., 2012).Retains the three CBFA2T3 N-terminal nervy homology regions (NHR) that mediate protein interactions and the five GLIS2 C-terminal domains (ZnF) responsible for interaction with DNA and transactivation. The MYND (myeloid, nervy, and Deaf-1 domain, class of zinc finger domain reported to interact with the N-CoR repressor complex) domain of CBFA2T3 is lost.

This fusion between two transcriptional regulators results in aberrant expression of genes controlled either by CBFA2T3 or GLIS2 (Thiollier et al., 2012).
There is an homogenous gene expression signature including a strong expression of CD56. Among the differentially regulated genes are known targets of the Hedgehog pathway including BMP2, BMP4, GATA3, and CCND2. CBFA2T3/GLIS2 induces BMP signaling. Hedgehog and JAK-STAT pathways are significantly upregulated (Gruber et al., 2012; Thiollier et al., 2012). CBFA2T3/GLIS2 cells demonstrated enhanced self-renewal in vitro (Gruber et al., 2012). Aurora A kinase (AURKA) inhibitors can induce differentiation and inhibits proliferation of AMKL blasts (Thiollier et al., 2012).

CBFA2T3/GLIS2 CBFA2T3 (16q24.3) GLIS2 (16p13.3) M|CBFA2T3/GLIS2 CBFA2T3 (16q24.3) GLIS2 (16p13.3) M inv(16)(p13q24)