Abstract Recent comprehensive genetic studies revealed numerous genetic aberrations underlying a group of high-risk leukemias that share a specific activated kinase gene expression pattern. These ...ALLs were first recognized by the expression profile similar to that of Philadelphia chromosome-positive ALL and currently can be sub-classified by the main aberrantly activated kinase in the leukemic cells. We herein review the biological mechanisms and diagnostic and clinical challenges presented by these leukemias.
Aneuploidy is one of the hallmarks of cancer. Acquired additions of chromosome 21 are a common finding in leukemias, suggesting a contributory role to leukemogenesis. About 10% of patients with a ...germ line trisomy 21 (Down syndrome) are born with transient megakaryoblastic leukemia. We and others have shown acquired mutations in the X chromosome gene GATA1 in all these cases. The gene or genes on chromosome 21 whose overexpression promote the megakaryoblastic phenotype are presently unknown. We propose that ERG, an Ets transcription factor situated on chromosome 21, is one such candidate. We show that ERG is expressed in hematopoietic stem cells, megakaryoblastic cell lines, and in primary leukemic cells from Down syndrome patients. ERG expression is induced upon megakaryocytic differentiation of the erythroleukemia cell lines K562 and UT-7, and forced expression of ERG in K562 cells induces erythroid to megakaryoblastic phenotypic switch. We also show that ERG activates the gpIb megakaryocytic promoter and binds the gpIIb promoter in vivo. Furthermore, both ERG and ETS2 bind in vivo the hematopoietic enhancer of SCL/TAL1, a key regulator of hematopoietic stem cell and megakaryocytic development. We propose that trisomy 21 facilitates the occurrence of megakaryoblastic leukemias through a shift toward the megakaryoblastic lineage caused by the excess expression of ERG, and possibly by other chromosome 21 genes, such as RUNX1 and ETS2, in hematopoietic progenitor cells, coupled with a differentiation arrest caused by the acquisition of mutations in GATA1.
The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest ...involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.
On the basis of epidemiological studies, infection was suggested to play a role in the etiology of human cancer. While for some cancers such a role was indeed demonstrated, there is no direct ...biological support for the role of viral pathogens in the pathogenesis of childhood leukemia. Using a novel bioinformatic tool that alternates between clustering and standard statistical methods of analysis, we performed a 'double-blind' search of published gene expression data of subjects with different childhood acute lymphoblastic leukemia (ALL) subtypes, looking for unanticipated partitions of patients, induced by unexpected groups of genes with correlated expression. We discovered a group of about 30 genes, related to the interferon response pathway, whose expression levels divide the ALL samples into two subgroups; high in 50, low in 285 patients. Leukemic subclasses prevalent in early childhood (the age most susceptible to infection) are over-represented in the high-expression subgroup. Similar partitions, induced by the same genes, were found also in breast and ovarian cancer but not in lung cancer, prostate cancer and lymphoma. About 40% of breast cancer samples expressed the 'interferon-related' signature. It is of interest that several studies demonstrated mouse mammary tumor virus-like sequences in about 40% of breast cancer samples. Our discovery of an unanticipated strong signature of an interferon-induced pathway provides molecular support for a role for either inflammation or viral infection in the pathogenesis of childhood leukemia as well as breast and ovarian cancer.
Stil (Sil, SCL/TAL1 interrupting locus) is a cytosolic and centrosomal protein expressed in proliferating cells that is required for mouse and zebrafish neural development and is mutated in familial ...microcephaly. Recently the Drosophila melanogaster ortholog of Stil was found to be important for centriole duplication. Consistent with this finding, we report here that mouse embryonic fibroblasts lacking Stil are characterized by slow growth, low mitotic index and absence of clear centrosomes. We hypothesized that Stil regulates mitosis through the tumor suppressor Chfr, an E3 ligase that blocks mitotic entry in response to mitotic stress. Mouse fibroblasts lacking Stil by genomic or RNA interference approaches, as well as E9.5 Stil⁻/⁻ embryos, express high levels of the Chfr protein and reduced levels of the Chfr substrate Plk1. Exogenous expression of Stil, knockdown of Chfr or overexpression of Plk1 reverse the abnormal mitotic phenotypes of fibroblasts lacking Stil. We further demonstrate that Stil increases Chfr auto-ubiquitination and reduces its protein stability. Thus, Stil is required for centrosome organization, entry into mitosis and cell proliferation, and these functions are at least partially mediated by Chfr and its targets. This is the first identification of a negative regulator of the Chfr mitotic checkpoint.
Mucormycosis is a life-threatening infection with a tendency for angioinvasion that may lead to progressive dissemination. Disseminated mucormycosis, defined as the involvement of two or more ...non-contiguous sites, is rare in children, and data concerning its management and outcome are scarce. The aim of this study was to assess the contemporary management strategies and outcomes of disseminated mucormycosis in the pediatric population.
We conducted a retrospective search in six large tertiary medical centers for all cases of disseminated mucormycosis that occurred between 2009-2020 in patients aged 1-20 years.
Twelve cases were identified. Underlying conditions included hematological malignancies (
= 10), solid tumor (post-autologous hematopoietic stem cell transplantations;
= 1), and solid organ (liver) transplantation (
= 1). In all cases, amphotericin B formulations were administered as first-line therapy; in eight cases, they were also administered in combination with an echinocandin or triazole. Seven patients underwent surgical debridement procedures. The six-week mortality was 58%. Among the patients diagnosed between 2009-2015, one of the six survived, and of those diagnosed between 2016-2020, four of the six were salvaged.
Disseminated mucormycosis is a life-threatening and often fatal disease, and improved diagnostic and therapeutic strategies are needed. Nevertheless, in this population-based study, five patients (42%) were salvaged through combined liposomal amphotericin/triazole treatment and extensive surgical interventions.
PDF
