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The molecular basis of susceptibility to childhood malignant hemopathy remains largely unknown. An excess of skeletal congenital anomalies has been reported among children with hematological malignancy and points towards involvement of developmental genes, like those belonging to the HOX gene family. In addition to their role in embryogenesis, HOX transcription factors are known to be regulators of proliferation and differentiation of hematopoietic cells. We aimed to explore the possibility that germline alterations of HOX genes might be involved in childhood acute lymphoid malignancies. A cohort of 86 children diagnosed with acute lymphoid malignancy was studied, 20 of them concurrently presenting a congenital anomaly of the skeleton. First, we screened for nucleotide changes throughout the HOX genes of paralogous groups 4 to 13 in the 20 patients with skeletal defects, following a skeletal phenotype-based strategy. Subsequently, we extended the HOX mutation screening to the other 66 children having a malignant lymphoproliferative disorder, but without skeletal defects. In total, 16 germline mutations were identified. While 13 changes were also observed in healthy controls, three variants were exclusively found in acute lymphoid malignancy cases. These comprised the germline c.242A>T (p.Glu81Val) missense mutation of HOXD4, detected in two children diagnosed with acute lymphoblastic leukemia (ALL). Furthermore, this mutation was found in association with other specific HOX variants of cluster D (2q31-q37), defining a unique haplotype. Functional analysis of the murine Hoxd4 homolog revealed that mutant Hoxd4 protein had lower transcriptional activity than wild-type protein in vitro. The p.Glu81Val mutation of HOXD4 thus results in a partial loss-of-function, which might be involved in childhood ALL.

Objective: Our aim was to investigate the effect of uterine contractions on free fetal DNA concentration in maternal plasma at term., Study Design: Nine pregnant women were admitted for elective induction of labour between 38 and 40 weeks of gestation. All patients carrying male fetuses and without history of pre-term labour and membrane rupture were selected. Maternal venous blood samples were serially collected every hour during labour, one hour after delivery and 24 h after delivery. In order to amplify fetal and total free DNA, primers for SRY and GAPDH genes were respectively chosen. Real- time PCR analysis was performed with an GeneAmp 5700 Sequence Detection System (Applied Biosystems Foster City, USA). Statistical significance was determined using the Wilcoxon test., Result: Median concentration of fetal DNA in plasma before labour was 3081 copies/mL (Range 812-15 864 copies/mL). No significant difference between the number of copies per millilitre before any contractions and during labour was demonstrated. One hour after delivery, significant decrease in the fetal DNA rate was observed with a median concentration of 293 copies/mL (Range 0-2037 copies/mL) (p-value: 0.04). This drop was more significant 24 h after delivery with a median concentration of 0 copies/mL (Range 0-95 copies/mL) (p-value: 0.02)., Conclusions: During labour, no changes in free fetal DNA in maternal plasma were demonstrated. This suggests that labour does not have effect on free fetal DNA release in maternal circulation at term., (Copyright 2003 John Wiley & Sons, Ltd.)

We here report the clinical, cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data on 14 patients with a myeloid malignancy and structural aberration of chromosome band 11q23 associated with overrepresentation or amplification of the MLL gene. The number of copies of MLL varied from three (two cases) to a cluster consisting of multiple hybridization spots. Together with previous reports, available data indicate that amplification of 11q23/MLL is a recurrent genetic change in myeloid malignancy. It affects mainly elderly patients and is often associated with dysplastic bone marrow changes or with complex karyotypic aberrations, suggestive of genotoxic exposure. It is associated with a poor prognosis. In addition, FISH analysis of nine cases with additional 11q probes showed that the overrepresented chromosomal region is generally not restricted to MLL, and Southern blot analysis indicated that amplification does not involve a rearranged copy of this gene. The significance of MLL amplification and the mechanisms by which it could play a role in leukemogenesis and/or disease progression remain to be elucidated., (Copyright 2000 Wiley-Liss, Inc.)