Sex chromosome loss may represent a disease-associated clonal population in chronic lymphocytic leukemia.

Whether sex chromosome loss (SCL) is an age-related phenomenon or a cytogenetic marker of hematological disease is unclear. To address this issue in chronic lymphocytic leukemia (CLL), we investigated 20 cases with X or Y chromosome loss detected by conventional cytogenetics (CC). The frequency of SCL was low in CLL (2.3%). It was the sole abnormality, as detected by CC, in 10/20 (50%) patients. Fluorescence in situ hybridization (FISH) analyses confirmed SCL in all patients tested, present in 5-88% of cells (median: 68%). Deletions of 13q were observed by FISH in 16/20 (80%) patients. Compared with CLL without SCL, SCL was significantly associated with 13q deletion, especially when bi-allelic (P = 0.04). Co-hybridization analyses showed that SCL could be a concomitant, primary or secondary change, or be present in an independent clone. FISH analyses were performed on blood sub-populations isolated by Ficoll or flow cytometry. Comparing mononuclear cells (including CLL cells) and polynuclear cells separated by Ficoll, a maximum of 2% of polynuclear cells were found with SCL, whereas mononuclear cells exhibited a significantly higher loss frequency (range: 6-87%) (P = 0.03). Comparing B-cells (including CLL cells) and T-cells sorted by flow cytometry, the proportion of B-CD19+ cells with SCL was significantly higher (range: 88-96%) than that observed in T-CD3+ cells (range: 2-6%) (P = 0.008). We conclude that SCL has to be considered as a clonal aberration in CLL that may participate in the oncogenic process.

Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5 in a B-cell chronic lymphoproliferative disorder.

Homeobox containing transcription factors are frequently deregulated in human hematologic malignant diseases either indirectly through an abnormality of an upstream factor, or directly through rearrangement of the gene itself. Study of T-cell acute lymphoblastic leukemia identified the related non-clustered homeobox transcription factors, TLX1 and TLX3, as frequently ectopically expressed as a result of chromosomal translocations. We report the deregulation of a non-clustered homeobox gene in a new type of t(5;14)(q35;q11) translocation in a mature peripheral B-cell leukemia. This translocation results in the ectopic expression of the CSX1/NKX2-5 gene on chromosome 5q35 due to its juxtaposition to the TCR delta gene on chromosome 14q11. Expression of the CSX1/NKX2-5 protein conferred enhanced replating potential to transduced murine bone marrow cells. Our study establishes that deregulation of homeobox encoding genes is not restricted to acute leukemic proliferations, but is also observed in chronic malignant diseases.

Erythroleukemia: a comparison between the previous FAB approach and the WHO classification.

Erythroleukemia is, within FAB classification, a proliferation of erythroblasts superior to 50% and of myeloblasts superior to 30%. The new WHO classification abolishes the frontier between RAEB-t with 20% and leukemia with 30% of blasts. AML6 variant is a new entity characterized by the proliferation of immature erythroblasts and the absence of non-erythroid blast cells. We analyzed 16 erythroleukemia, 5 RAEB-t and 2 AML6 variants to clarify their relationship. We suggest on survival, karyotype and cytologic characteristics that secondary erythroleukemia are the same entity as RAEB-t, confirming the WHO classification and that amongst de novo erythroleukemia, there is 'AML6 variant' with pure erythroid lineage proliferation.

[Chronic myeloid leukemia with variant e19a2 BCR-ABL1 fusion transcript: interest of the molecular identification at diagnosis for minimal residual disease follow-up]. / Leucémie myéloïde chronique avec transcrit de fusion variant BCR-ABL1 e19a2 : intérêt de l'identification moléculaire au diagnostic pour le suivi de la maladie résiduelle.

We report here the case of a sixty-eight-year old woman with chronic myeloid leukemia. Molecular techniques identified the presence of the rare e19a2 BCR-ABL1 transcript. The patient was treated by 1(st) generation tyrosine-kinase inhibitor (TKI) (imatinib). Disease monitoring was performed by cytogenetic analyses and quantification of the BCR-ABL1 transcript. After 3 months, the treatment was modified due to an absence of biological response and poor tolerance. After 21 months with 2nd generation TKIs (nilotinib), the patient was responding optimally to treatment, with a complete cytogenetic response and a major molecular response. This observation emphasizes the importance of determining the chromosomal breakpoints at diagnosis to enable adequate molecular monitoring of residual disease. Careful monitoring of minimal residual disease is important to thoroughly assess the response to treatment, detect resistance and adapt the therapeutic strategy. The kinetics and the depth of the response to TKI also represent major prognostic factors. Molecular monitoring is performed using real-time quantitative PCR, which has to be adapted to each type of transcript. For rare BCR-ABL1 transcripts, an international standardization, as it is developed for conventional transcripts, is lacking. Yet, such a harmonization would be useful to assess in an optimal and large scale way the response to TKI in these patients, and to determine what the best management is.

Prognostic impact of JAK2V617F mutation in myelodysplatic syndromes: A matched case control study.

While in RARS-T, JAK2V617F mutation is common and associated with good prognosis, the clinical and prognostic impact of this mutation in other MDS is unknown. We collected data from 132 non-RARS-T MDS with known JAK2V617F mutation status. JAK2V617F mutation was significantly correlated with lower progression to AML (p<.0011) and better overall survival (OS, p=.011). OS difference persisted after matching on age, sex, IPSS and % marrow blast (p=.031). Thus, in MDS other than RARS-T, JAK2V617F mutation may be associated with favorable outcome.

Trisomy 4 associated with double minute chromosomes and MYC amplification in acute myeloblastic leukemia.

A case of de novo acute myeloblastic leukemia (AML) M2, with trisomy 4 and double minute (dmin) chromosomes is reported. Amplification of the MYC gene ascertained by FISH was associated with dmin. A review of the literature of trisomy 4-dmin-associated AML shows that this entity preferentially occurs in elderly women and is not always associated with previously identified exposition to mutagens.