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Young patients with neurofibromatosis type 1 (NF1) are at increased risk of developing various malignancies, most of which are myeloid disorders. The observed loss of NF1 allele in the myeloid malignancies of NF1 patients suggests a role of NF1 as a tumor suppressor gene. Loss of 17p was found to be quite frequent in neural crest tumors from patients with NF1, raising the possibility of p53 tumor suppressor gene involvement in other NF1-related tumors.The authors studied mutations in the NF1 and p53 genes, using loss of heterozygosity, single strand conformation polymorphism, heteroduplex and sequencing analyses.An NF1 germline mutation was identified in exon 31 of a child who developed juvenile chronic myelogenous leukemia (JCML). The mutation was segregated within the proband's family. A 14bp deletion at exon 6 of the p53 gene was observed when JCML was diagnosed, and the wild-type p53 allele was lost during progression of the disease. No loss of the normal NF1 allele could be detected.A germline mutation in the NF1 gene and sequential inactivation of p53 alleles in the malignant clone of JCML raise the possibility of a correlation between NF1 and p53 genes in the tumorigenesis of JCML.

It has been suggested that the malignant transformation, in some of the acute leukemias, may involve totipotent stem cells resulting in a biphenotypic leukemia expressing both myeloid, and lymphoid characteristics. We describe here a hybrid cell acute leukemia, in a 16-day-old infant, in whom leukemic cells coexpressed myeloid and lymphoid B cell antigens. Blast cells in the bone marrow showed L2 morphology according to the French American British (FAB) classification, with positive periodic-acid Schiff, and nonspecific esterase staining. Sudan black, and specific esterase were negative. Terminal deoxynucleotidyl transferase, was strongly positive in 5% of blasts, and faintly reactive with the rest. Karyotypic analysis demonstrated a translocation of t(11:17);(q23;p13). Immunoglobulin gene analysis revealed rearrangement of the heavy chain genes. The blasts' phenotype was HLA/DR+ B4+ My7+ My9+ common acute lymphoblastic leukemia antigen (CALLA) B1- T11-. Dual immunofluorescence staining using anti My7, and My9 fluorescein isothiocyanate, and anti B4 pycoerythrin conjugated monoclonal antibodies, and flow cytofluorometry, revealed a labeling pattern of 25% B4+; 10% to 15% My7+; 17% My9+; and 50% of cells coexpressing B4 My7, and My9 antigens. These results provide evidence for a hybrid leukemia with lymphomyeloblasts being part of a single clone, which may indicate the origin of this leukemic clone from a pluripotent (lymphoid/myeloid) stem cell.

Clinical features, leukemic cell characterization, chromosomal findings, and treatment outcome were analyzed in a retrospective study of 30 cases with acute leukemia of infancy, 24 infants with acute lymphoblastic leukemia (ALL), and six cases with acute nonlymphoblastic leukemia (ANLL). Extensive bulky disease with organomegaly, central nervous system (CNS), and skin involvement were prominent features at diagnosis with a higher frequency in ANLL as compared to ALL. Four of six ANLL patients were classified as monocytic or myelomonocytic. In the ALL group nine of 24 (36%) were non-L1 morphology and six of 17 (33%) were common ALL antigen (CALLA) negative, the majority of them (five of six) were included in the non-L1 group. Immunophenotyping revealed four cases with early B-cell (three patients: Ia+B4+, and one patient: Ia+) and two cases with T-cell. Mixed lineage leukemia was found in five infants. Heavy chain immunoglobulin gene rearrangement was present in six cases tested, two CALLA+, two with Ia+B4+, and two were undifferentiated mixed lineage leukemia. Chromosomal aberrations were detected in ten of 18 patients, mostly in ANLL and CALLA negative ALL. Translocations were detected in six patients, involving 4q21-23 and 11q23 in three and two cases, respectively. The probability of five-year DFS were 27% for the whole group. The worst prognosis was observed in infants younger than 6 months of age, in whom the leukemia cell characteristics was compatible with stem cell: ANLL, very early pre-B, or undifferentiated mixed type. The chromosomal aberrations found in all cases included translocation with the seemingly nonrandom breakpoints at 4q21 and 11q23, and breakpoints that corresponded to known fragile sites. This finding may be suggestive of an underlying genetic predisposition associated with the poor prognosis of leukemia of infancy.