NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice

Here we describe hemopoietic chimeras serving as a mouse model for NUP98-HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98-HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.     

The oncofetal gene Pem specifies a divergent paired class homeodomain.

The polypeptide sequence predicted from the Pem oncofetal gene cDNA contains a homeodomain most closely related to the paired class. Pem, paired class member orthodenticle, and the bicoid maternal gene product homeodomains all have lysine residues at a recognition helix position implicated in DNA-binding specificity. The Pem recognition helix also has an isoleucine residue replacing an invariant asparagine residue and shares an asparagine residue at a third position with two other vertebrate homeoproteins, at least one of which binds to DNA only as a dimer.     

Geographic heterogeneity of the AML1-ETO fusion gene in Iranian patients with acute myeloid leukemia

Background:

The human AML1 gene, located on chromosome 21, can be fused to the AML1- eight-twenty-one (ETO) oncoprotein on chromosome eight, resulting in a t(8;21)(q22;q22) translocation. Acute myeloid leukemia (AML) associated with this translocation is considered a distinct AML with a favorable prognosis. Due to the various incidences of the translocation, which is associated with geographic diversities, investigation of molecular epidemiology is important to increase the awareness of physicians and hematologists regarding the frequency this chromosomal aberration.

Methods:

The patients were classified according to the French–American–British classification into eight groups: M0–M7. Determination of the prevalence of the AML1-ETO fusion gene was accomplished by TaqMan real-time PCR. Bone marrow samples from 113 patients with newly-diagnosed, untreated AML -M1, -M2, and -M4, and 20 healthy controls admitted to the Ghaem Hospital in Mashhad, Iran were studied.

Results:

The AML1-ETO fusion gene was detected up 50% of the M2 subgroup and absent in the M1 and M4 subtypes and healthy controls. Comparison of the prevalence of the t(8;21) translocation with results of previous studies showed that it varies between countries. This result may be due to geographic or ethnic differences, or both.

Conclusions:

The relatively high prevalence of the t(8;21) translocation in Iran was similar to that found in other Asian countries. It was closely associated with female gender, relatively young age, and FAB-M2 subtype. Its distribution varied considerably with geographic area. Therefore, further studies are needed to provide epidemiological data important for the establishment of optimal therapeutic strategies applicable to patients of each region. Key Words: Acute myeloid leukemia, AML1-ETO, M2, Prevalence, t(8;21)     

Acquired pericentric inversion of chromosome 9 in acute myeloid leukemia

Pericentric inversion of chromosome 9 involving the qh region is relatively common as a constitutional genetic aberration without any apparent phenotypic consequences. However, it has not been established as an acquired abnormality in cancer. Among the three patients reported so far in the literature with acquired inv(9), only one had acute myeloid leukemia (AML). Here we describe an unique case where both chromosomes 9 presented with an acquired pericentric inversion with breakpoints at 9p13 and 9q12 respectively, in a AML patient with aberrant CD7 and CD9 positivity. Additionally, one der(9) also showed short arm deletion at 9p21 to the centromeric region and including the p16 gene. The constitutional karyotype was normal. This is probably the first report describing an acquired inv(9) involving both chromosomes 9 in AML. The possible significance of this inversion is discussed.     

NEDD9 overexpression: Prognostic and guidance value in acute myeloid leukaemia

It has been demonstrated that neural precursor cell expressed developmentally downregulated protein (NEDD) plays crucial roles in tumorigenesis and may serve as potential biomarkers in cancer diagnosis and prognosis. However, few studies systematically investigated the expression of NEDD family members in acute myeloid leukaemia (AML). We systemically determined the expression of NEDD family members in AML and determined their clinical significance. We identified that NEDD9 expression was the only member among NEDD family which was significantly increased in AML. NEDD9 overexpression was more frequently classified as FAB-M4/M5 (p = 0.008 and 0.013, respectively), hardly as FAB-M2/M3. Moreover, NEDD9 overexpression was significantly associated with complex karyotype and TP53 mutation. The significant association between NEDD9 overexpression and survival was also observed in whole-cohort AML and non-M3 AML patients. Notably, AML patients with NEDD9 overexpression may benefit from hematopoietic stem cell transplantation (HSCT), whereas those cases without NEDD9 overexpression did not. Finally, a total of 822 mRNAs and 31 microRNAs were found to be differentially expressed between two groups. Among the microRNAs, miR-381 was also identified as a microRNA that could direct target NEDD9. Taken together, our findings demonstrated that NEDD9 overexpression is associated with genetic abnormalities as well as prognosis and might act as a potential biomarker guiding the choice between HSCT and chemotherapy in patients with AML after achieving complete remission.     

Differential regulation of rat beta-casein-chloramphenicol acetyltransferase fusion gene expression in transgenic mice.

Previous studies in our laboratory have demonstrated the mammary-specific expression of the entire rat beta-casein gene with 3.5 kilobases (kb) of 5' and 3.0 kb of 3' DNA in transgenic mice (Lee et al., Nucleic Acids Res. 16:1027-1041, 1988). In an attempt to localize sequences that dictate this specificity, lines of transgenic mice carrying two different rat beta-casein promoter-bacterial chloramphenicol acetyltransferase (cat) fusion genes have been established. Twenty and eight lines of transgenic mice carrying two fusion genes containing either 2.3 or 0.5 kb, respectively, of 5'-flanking DNA of the rat beta-casein gene along with noncoding exon I and 0.5 kb of intron A were identified, most of which transmitted the transgenes to their offspring in a Mendelian pattern. CAT activity was detected predominantly in the lactating mammary gland of female transgenic mice but not in the male mammary fat pad. A several-hundred-fold variation in the level of cat expression was observed in the mammary gland of different lines of mice, presumably due to the site of integration of the transgenes. CAT activity was increased in the mammary gland during development from virgin to midpregnancy and lactation. Unexpectedly, the casein-cat transgenes were also expressed in the thymus of different lines of both male and female mice, in some cases at levels equivalent to those observed in the mammary gland, and in contrast to the mammary gland, CAT activity was decreased during pregnancy and lactation in the thymus. Thus, 0.5 kb of 5'-flanking DNA of the rat beta-casein gene along with noncoding exon I and 0.5 kb of intron A are sufficient to target bacterial cat gene expression to the mammary gland of lactating mice.     

Pathogenic pathways in acute myeloid leukemias.

Despite the common clinical, hematological and prognostic features that define acute myeloid leukemia (AML) there is considerable heterogeneity among individual cases, suggesting different pathogenic pathways. Based on a simple theoretical model, according to the vital characteristics of the leukemic clone (proliferative rate and resistance to apoptosis) we propose a classification of AML into two broad categories: a) high leukemic clone vitality (HLV) AML, corresponding roughly to the World Health Organization (WHO) classification group of entities "AML with recurrent cytogenetic abnormalities" and b) low leukemic clone vitality (LLV) or "opportunistic" AML corresponding to the WHO groups "AML with multilineage dysplasia" and "therapy-related AML". HLV-AML leukemic clones are characterized by rate-limiting genomic mutations capable of conferring proliferation/survival advantage over a normal hematopoietic environment while in LLV-AML, the leukemic clones are not particularly proliferative or apoptosis-resistant, but are nevertheless selected against an impaired, previously damaged hematopoietic environment. Such a pathogenesis-oriented classification might have therapeutic and prognostic implications, providing a theoretical basis for a further adaptation of the current standard treatment strategies to the individual characteristics of the AML patients.     

The lytB gene of Escherichia coli is essential and specifies a product needed for isoprenoid biosynthesis.

LytB and GcpE, because they are codistributed with other pathway enzymes, have been predicted to catalyze unknown steps in the nonmevalonate pathway for isoprenoid biosynthesis. We constructed a conditional Escherichia coli lytB mutant and found that LytB is essential for survival and that depletion of LytB results in cell lysis, which is consistent with a role for this protein in isoprenoid biosynthesis. Alcohols which can be converted to pathway intermediates beyond the hypothesized LytB step(s) support limited growth of E. coli lytB mutants. An informatic analysis of protein structure suggested that GcpE is a globular protein of the TIM barrel class and that LytB is also a globular protein. Possible biochemical roles for LytB and GcpE are suggested.     

Prognostic role of Wnt and Fzd gene families in acute myeloid leukaemia

Wnt-Fzd signalling pathway plays a critical role in acute myeloid leukaemia (AML) progression and oncogenicity. There is no study to investigate the prognostic value of Wnt and Fzd gene families in AML. Our study screened 84 AML patients receiving chemotherapy only and 71 also undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) from the Cancer Genome Atlas (TCGA) database. We found that some Wnt and Fzd genes had significant positive correlations. The expression levels of Fzd gene family were independent of survival in AML patients. In the chemotherapy group, AML patients with high Wnt2B or Wnt11 expression had significantly shorter event-free survival (EFS) and overall survival (OS); high Wnt10A expressers had significantly longer OS than the low expressers (all P < .05), whereas, in the allo-HSCT group, the expression levels of Wnt gene family were independent of survival. We further found that high expression of Wnt10A and Wnt11 had independent prognostic value, and the patients with high Wnt10A and low Wnt11 expression had the longest EFS and OS in the chemotherapy group. Pathway enrichment analysis showed that genes related to Wnt10A, Wnt11 and Wnt 2B were mainly enriched in ‘cell morphogenesis involved in differentiation’, ‘haematopoietic cell lineage’, ‘platelet activation, signalling and aggregation’ and ‘mitochondrial RNA metabolic process’ signalling pathways. Our results indicate that high Wnt2B and Wnt11 expression predict poor prognosis, and high Wnt10A expression predicts favourable prognosis in AML, but their prognostic effects could be neutralized by allo-HSCT. Combined Wnt10A and Wnt11 may be a novel prognostic marker in AML.