Molecular Cytogenetic Approach to Characterize Novel and Cryptic Chromosome Abnormalities in Childhood Myeloid Malignances of Fanconi Anemia

Abstract

Myeloid malignancies can be either primary or secondary, whether or not a specific cause can be determined. Fanconi anemia (FA), a rare constitutional bone marrow failure, usually presents an increased possibility of clonal evolution, due to the increase in chromosomal instability, TP53 activation, and cell death. The evolution of FA may include aplastic anemia by the progressive failure of the bone marrow and myelod neoplasias, such as acute myeloid leukemia and myelodysplastic syndrome. Chromosome abnormalities, particularly of chromosomes, 1, 3, and 7, during the aplastic phase of the disease are predictive of evolution to acute myeloid leukemia/myelodysplastic syndrome. Cytogenetic studies are indispensable to characterize chromosome abnormalities, and thus an important part of the clinical management, and for planning of therapeutic interventions. Here, clinical data and outcomes of 4 FA, 3 of them with myeloid malignances and 1 asymptomatic, and detailed characterization of their chromosome abnormalities using cytogenetics techniques are described.

Clinical and cytogenetic profile of Fanconi anemia diagnosed after implementation of mitomycin C cytogenetic test in the state of Pernambuco, Brazil

“…Borges et al . 24 reported four patients with FA undergoing transformation to MDS (three cases) and AML (one case) who showed chromosomal changes in the BM, one being recurrent and the others, new translocations. Acquired chromosomal changes are the main indication for BM transplantation and the main changes described are losses and gains in the 1q, 3q, and 11q regions, as well as in -7 and +8.…”

Cytogenetic Aberrations in Patients with Aplastic Anemia

“…Tespit ettiğimiz -7, +8, -20 bulguları, literatürde AA hastalarında görülen kromozom düzensizlikleri olarak bildirilmiştir. [11][12][13][14] Özellikle monozomi 7 ve trizomi 8'in en sık gözlenen kromozom sayı düzensizlikleri olduğu çeşitli çalışma grupları tarafından bildirilmiştir. 14,15 dir.…”

An uncommon t(9;11)(p24;q22) with monoallelic loss of ATM and KMT2A genes in a child with myelodysplastic syndrome/acute myeloid leukemia who evolved from Fanconi anemia

“…In our study, the FISH analysis also showed the monoallelic loss of the KMT2A gene. The KMT2A locus is involved in more than 60 different chromosomal translocations in pediatric acute leukemias [ 17 ]. In AML, the t(9;11) usually results from KMT2A gene translocation, being the (p22;q23) the breakpoint frequently described [ 11 ].…”

“…The ATM gene acts on the regulation of the cell cycle after a DNA damage is recognized [ 15 , 16 ]. On the other hand, the KMT2A gene encodes a protein that is involved in chromatin remodeling and positively regulates multiple homeobox transcription factors, also it is highly associated with the development of AML [ 17 ].…”

“…Given the high incidence of hematological complications of FA patients, BM surveillance for morphological and cytogenetic changes provides an important contribution to the clinical decision [ 11 ]. However, there are only a few studies in patients with FA showing the bone marrow chromosomal alterations analyzed by classical and molecular cytogenetics associated with evolution to MDS and AML [ 13 , 14 , 17 – 19 ]. Here, we describe an uncommon yet unreported t(9;11)(p24;q22) with monoallelic loss of ATM and KMT2A genes, defined by classical cytogenetic and FISH analysis, in a child with MDS/AML who evolved from FA associated with poor clinical outcome.…”