Common Leukemia- and Lymphoma-Associated Genetic Aberrations in Healthy Individuals

Abstract

Leukemia-and lymphoma-associated (LLA) chromosomal rearrangements are critical in the process of tumorigenesis. These genetic alterations are also important biological markers in the diagnosis, prognosis, and treatment of hematopoietic malignant diseases. To detect the presence or absence of these genetic alterations in healthy individuals, sensitive nested RT-PCR analyses were performed on a large number of peripheral blood samples for selected markers including MLL partial tandem duplications (PTDs), BCR-ABL p190, BCR-ABL p210, MLL-AF4, AML1-ETO, PML-RARA, and CBFB-MYH11. Using nested RT-PCR, the presence of all of these selected markers was detected in healthy individuals at various prevalence rates. No correlation was observed between incidence and age except for BCR-ABL p210 fusion, the incidence of which rises with increasing age. In addition, nested RT-PCR was performed on a large cohort of umbilical cord blood samples for MLL PTD, BCR-ABL p190 and BCR-ABL p210. The results demonstrated the presence of these aberrations in cord blood from healthy neonates. To our knowledge, the presence of PML-RARA and CBFB-MYH11 in healthy individuals has not been previously described. The present study provides further evidence for the presence of LLA genetic alterations in healthy individuals and suggests that these mutations are not themselves sufficient for malignant transformation.

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features

“…Therefore, a clear distinction of de novo AML and CML blast crisis remains challenging even in these inv(16)+ cases. The distribution of BCR-ABL p190 and p210 in inv(16)-CBF-AML was notably different from CML blast crisis: 53 % (9 cases) carried the p190 transcript in AML, whereas p190 was only found in one of 19 published cases of CML-AP/BC with inv (16) [18,19,[39][40][41][42][43][44][45][46][47][48]. Therefore, the detection of the minor BCR-ABL transcript in AML with inv(16) might be helpful in identifying de novo BCR-ABL+ AML.…”

“…It is well known that BCR-ABL may also temporarily occur at very low levels in the blood of healthy individuals [14][15][16][17]. The co-incidence of spontaneously occurring BCR-ABL within clonal hematopoiesis could possibly explain the development of a BCR-ABL+ AML and the underlying Bmutational background^; the maturation stage of the affected cell might decide whether the additional acquisition of BCR-ABL leads to AML, CML, or just a very small and only temporarily detectable BCR-ABL+ subclone.…”

Cancer-Associated Mutations in Healthy Individuals: Assessing the Risk of Carcinogenesis

“…Although some studies suggest an age-dependent increase in the frequency of t(14;18)-positive cells among healthy individuals (40,41), most studies show no association with age (42)(43)(44), including one with a large sample of 204 individuals (5). If all mutations resulting in t(14;18) translocations were always persistent, one should expect to see a clear correlation between its incidence and age.…”

Analysis of Leukemogenic Gene Products in Hematopoietic Progenitor Cells

“…Further evidence of this concept has been demonstrated by gene expression analysis of healthy individuals. Here, oncogenes such as BCR/ABL and AML1/ETO have been frequently detected in individuals completely lacking any sign of disease (Song et al, 2011). As CD34+ cells represent the human hematopoietic stem/progenitor cell population, these cells can be regarded as appropriate target cells used to study the biological effects of oncogenes in human leukemia development.…”