Complex karyotype defined by molecular cytogenetic FISH and M-FISH in an infant with acute megakaryoblastic leukemia and neurofibromatosis

Abstract

Acute myeloid leukemia in childhood is a heterogeneous group of diseases, and different epidemiologic factors are involved in the etiopathogenesis. Genetic syndromes are one of the predisposing factors of acute myeloid leukemia (AML), including Down syndrome, Bloom syndrome, and neurofibromatosis. Acute megakaryoblastic leukemia (AMKL) is the main subtype in Down syndrome infants, and acquired chromosomal anomalies are closely related to the physiopathology of the illness. The main chromosomal anomalies in AMKL are structural, such as t(1;22); however, complex karyotypes are also common. Here we describe the case of an infant with neurofibromatosis developing AMKL with a complex karyotype including 5q and 17q deletions, TP53 deletion, and an unusual unbalanced chromosomal translocation t(11;19)(q13;p13), leading to three copies of the MLL gene.

Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models

“…Interestingly, Hedgehog pathway stimulation was shown to increase megakaryocyte differentiation of CD34 + hematopoietic cells (Martínez et al, 2006), and BMP4 was reported to be involved in TPO signaling and to play an important role in megakaryopoiesis (Jeanpierre et al, 2008), suggesting that aberrant activation of Hedgehog target genes by the CBFA2T3-GLIS2 fusion participates in the association between this fusion gene and megakaryoblastic leukemia. Together with previous studies (Borkhardt et al, 1995;Allen et al, 1998;Morerio et al, 2005;Bourquin et al, 2006;van Zutven et al, 2006;Takita et al, 2009;Marques-Salles et al, 2010), our genetic data indicate that non-DS AMKL can be divided into at least four molecular subgroups including patients with the OTT-MAL fusion, CBFA2T3-GLIS2 fusion, acquired trisomy 21 with a GATA1 mutation, and patients presenting a molecular signature of HOX A gene cluster activation including MLL or NUP98 alterations.…”

“…First, we characterized two patients with a NUP98-KDM5A fusion identical to a previously identified chromosomal translocation invisible by classical cytogenetics in AML (van Zutven et al, 2006) and an MLL-AF9 fusion in another non-DS AMKL patient. Although these fusions are rare in non-DS AMKL (8% and 4%, respectively in our cohort), MLL and NUP98 alterations were previously reported in AMKL (Borkhardt et al, 1995;Allen et al, 1998;Morerio et al, 2005;van Zutven et al, 2006;Takita et al, 2009;Marques-Salles et al, 2010). Both mutations result in deregulation of HOX A cluster genes, respectively, through recruitment of the histone H3K79 methyltransferase DOT1L by several MLL fusions (Nguyen and Zhang, 2011) and through recruitment of the histone acetyltransferase CBP/p300 and prevention of differentiation-associated removal of H3K4me3 by NUP98 fusions (Wang et al, 2009).…”