Chromatin Texture and Molecular Features Are Independent Prognostic Factors In AML

Abstract

4850 Introduction: The WHO 2008 classification of acute myeloid leukemia (AML) is based on morphology, cytogenetics and molecular features. Among them, mutations and internal tandem duplications of FLT3 in AML with a normal karyotype have been associated to a poor prognosis. Mutated NPM1 in the absence of FLT3-ITD is associated to a favorable. On the other hand, variables of nuclear chromatin texture have been described as independent risk factors in several malignancies (ALL, melanoma and multiple myeloma). Aim: To compare the influence on overall survival of the chromatin fractal dimension and molecular features in adult patients with AML. Patients and Methods: We analyzed 106 consecutive cases diagnosed at our Institution between 2007 and 2009. Diagnosis was made by bone marrow (BM) cytology and karyotype, and cases were classified by WHO criteria. Genomic DNA was extracted by phenol-chloroform. Genotyping was made with the MegaBACE 1000 equipment and analyzed in the Fragment Profiler v1.2. For detection of the FLT3-TKD mutation, genomic DNA was amplified by PCR followed by restriction analysis. Blasts from the diagnostic BM cytology were digitalized, segmented and nuclear morphometric variables were examined. Their influence on overall survival was analyzed in the Cox model. Results: Median age: 52 years; peripheral blood (PB) leukocytes: 24.0×109/l (0.7-281.3). In the univariate analysis were significant: PB leukocyte count (p=0.005), low-risk karyotype (p=0.002), FLT3 ITD+ (p=0.002), FLT3+NPM1- (p=0.029) and “goodness of fit” (R245) of the chromatin fractal dimension (Minkowski) (p=0.03). Age, fractal dimension and methylation status of p15, p16, p57, p73, ER and MDR1 were not significant. In the multivariate analyses including age, PB leukocytes, R245 and mutations, high leukocyte counts (p=0.03) and low R245 (p=0.01) were independent unfavorable and FLT3-NPM1- (p=0.04) and FLT3-NPM1+ (p=0.02) were favorable prognostic variables. Conclusions: The blast chromatin texture measured by R245 was an independent prognostic factor together with known risk variables in AML. Supported by: FAPESP and CNPq Disclosures: No relevant conflicts of interest to declare.

Molecular characteristics and chromatin texture features in acute promyelocytic leukemia

“…Therefore, it would be interesting to study the relation of these features with molecular characetristics of this disease. Nuclear texture features of neoplastic cells have shown to be morphological correlates of chromatin remodelling with genetic and epigenetic alterations in acute leukemias [ 12 - 17 ], and have shown to be related to patients’ survival. Recently, computerized image analysis has been used to examine chromatin remodeling in several hematological neoplasms and texture variables of the nuclear architecture have shown to be independent prognostic factors in acute leukemias [ 16 - 18 , 23 , 26 , 27 , 29 ].…”

“…Recently, the importance of epigenetic changes for normal hemopoietic maturation as well as in the pathogenesis of AML has been emphasized [ 14 , 17 - 19 ]. Hypermethylation of CpG islands within the promoter regions together with deacetylation of certain histones is an important mechanism of gene silencing in hematologic neoplasias.…”