PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.

It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.

[Apoptosis (programmed cell death) in the immune system and hemopoiesis]. / Apoptoza (programowana smierc komórki) w ukladzie immunologicznym i hemopoezie.

Apoptosis, or programmed cell death, is a series of controlled sequential events resulting in the demise of cells without evoking an inflammatory response. Although first described 20 years ago, this phenomenon evokes now renewed interest in this phenomenon, particularly in the light of our greater understanding of cellular signalling pathways and their genetic control. This is especially pertinent to haemopoiesis and overall maintenance of a functional immune system.

[The frequency of cytomegalovirus infection (CMV) in patients immunocompromised patients with malignant and nonmalignant blood disorders]. / Czestosc zakazenia wirusem cytomegalii (CMV) u chorych z niedoborem immunologicznym w przebiegu zlosliwych i niezlosliwych chorób krwi.

Studies on CMV infection were carried out in a group of 110 patients, aged from 15 to 78 (average 38), treated in the Department of Haematology. During the course of observation most of the patients were examined repeatedly. Diagnosis was based on serology (CFT, ELISA) and virus isolation from the clinical material. Primary infection (seroconversion) was confirmed in 4 (21%) out of 19 seronegative patients. Seropositive patients comprised 83 per cent. Active CMV infection was determined in 20 (22%) of those patients.

Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.