Analysis of CNV in the Genomes of the Marrow Cells of the Patients with AML Revealed That High Numbers of Aberrations Associate with Better Survival and Deletions with the Aberrant Expression of CD19 in the Leukemic Blasts
Authors: Jaskula Emilia , Lange Janusz , Mordak-Domagala Monika , Sedzimirska Mariola , Lemieszewska Marta , Tarnowska Agnieszka , Pakos Helena , Sobczynska-Konefal Anna , Lange Andrzej 
Published: November 2019

In our previous study (Jaskula et al., Blood 2017 130:1420) we reported that the number of CNVs within the KANSL1 gene was associated with the phenotype of AML. In the present study we looked at the presence of CNV across the whole genome.
One hundred and twenty seven AML patients (diagnosed according to the FAB/WHO criteria, F/M=62/65, age median: 57, range: 21 - 84 years) were included to the present study. The patients were genetically analysed including GTG karyotyping and/or FISH for X or Y deletion, inv (3), -5/5q-, -7/7q-,+8, MLL, RUNX1, PML/RARA or RARA, inv(16). In all patients the microarray analysis of the bone marrow cells having blasts cells (median value 56%) at diagnosis Agilent - Catalog Agilent Cancer CGH+SNP 180K (74 patients) or Roche - WG Catalog NimbleGene 12x270K (53 patients) microarrays were employed and the results were analysed with the use the Partek software employing the Partek Hidden Markov Model (HMM) and segmentation algorithms.
Results:
The number of CNV in M0 AML marrow cells was significantly lower (median: 0 aberration), as compared to secondary to MDS AML (median: 4.5 aberrations, p=0.006).
Patients with AML subtypes from M1 to M6 had higher number of CNV amplifications (median: 2) as compared to the patients with minimally differentiated blasts (M0, median: 0 amplifications, p=0.030).
Knowing that (i) changes in the chromatin structure may be associated with the CNV prevalence within the genome (Gheldof et al., PLoS One. 2013 Nov 12;8(11):e79973) and (ii) the aberrant expression of CD19 in AML blasts results from the chromatin structure variations (Walter et al., Oncogene. 2010 May 20;29(20):2927-37) we looked at the presence of association between the numbers of CNV and the presence of the aberrant CD19 expression in the leukemic blasts. It appeared that 11 AML patients having aberrant expression of CD19 (within whom 4 had t(8:21)) had more frequently CNV deletions than those lacking this aberrant expression (median: 2 vs 1 deletions, p=0.018, HMM algorithm).
Having the survival curves of the patients plotted accordingly to the high and low numbers of CNV, the situation is more complex and shows that: the patients having higher numbers of CNV aberrations (exceeding the mean of the whole group +SD) enjoyed better survival (20% vs 11%, p=0.090) when segmentation algorithm was employed. HMM analysis also suggested that the higher values of CNV (amplifications, exceeding the mean of the whole group +SD) was associated with better 5-year survival as compared to those with low numbers (42% vs 20%, ns).
The aberrant expression of CD19 analysis was associated with higher numbers of deletions (see above) and with better 5-year survival than those lacking this aberrant expression (45% vs 20%, p=0.064).
In conclusion, the prevalence of CNV within the genome shapes the phenotype of the leukemia and facilitates the survival.

Disclosures
No relevant conflicts of interest to declare.