Abnormalities of the p53 gene in juvenile myelomonocytic leukaemia

Abstract

Juvenile chronic myelomonocytic leukaemia (JMML) is a rare myeloproliferative disorder of childhood. Fewer than 30% of cases of JMML terminate in a blast crisis; however, its molecular mechanism is unknown. Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult‐type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis). Exons 4–8 of the p53 gene, which cover all the hot spots of point mutations, were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single‐strand conformation polymorphism analysis. No mobility shift of single‐strand DNA of PCR products in polyacrylamide gel electrophoresis, indicating point mutations, was found in 19/20 patients. DNA of the remaining patient in the chronic phase failed to be amplified by PCR and Southern blot analysis with XbaI‐digested genomic DNA revealed a gross rearrangement (presumed deletion) of the p53 gene. These data indicate that abnormalities of the p53 gene are rare in JMML and not responsible for acute transformation, but could be involved in the pathogenesis of some cases of JMML.

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

“…[22][23][24][25][26][27][28] Here we report a RAS mutation frequency of approximately 14% in a large (n>100) cohort of infant ALL cases, and a frequency of approximately 24% in infant ALL patients carrying MLL translocation t(4;11). These results are not consistent with previously published studies that reported either high RAS mutation frequency of 50%, or a total absence of RAS mutations in MLL-rearranged ALL.…”

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

“…NF1 wild type allele is frequently deleted and the Ras genes never mutated in children with neuro®bromatosis. In contrast, Ras mutations exist in patients with myeloid tumors that do not have neuro®bromatosis Neubauer et al, 1991;Miyauchi et al, 1994). A mutual exclusion e ect may indicate that both mutations are able, on their own, of fully activating the Ras proliferative pathway and, therefore, an additional mutation would not provide increased proliferative capacity.…”

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

“…35% of JMML patients have mutations in SHP2 (12)(13)(14), a protein-tyrosine phosphatase that positively regulates the RAS signaling pathway (15,16). RAS-activating mutations account for another 20 -25% of JMML-associated mutations (17)(18)(19). Several groups determined that a proportion of JMML patients have 11q uniparental disomy.…”