Christine Perot

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.

PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation

PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation

t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Francais de Cytogenetique Hematologique (GFCH)

To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children ⩽15 years and 153 adults), and 67 (18.5%) [47 children (22.4%) and 20 adults (13.1%)] were shown to either harbor the t(5;14)q35;q32) translocation or express the HOX11L2 gene or both. Most of the common hematological parameters did not show significant differences within positive and negative populations, whereas the incidence of CD1a+/CD10+ and cytoplasmic CD3+ patients was significantly higher in positive than in negative children. Out of the 63 positive patients investigated by conventional cytogenetics, 32 exhibited normal karyotype, whereas the others 31 showed clonal chromosome abnormalities, which did not include classical T-ALL specific translocations. Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients. Our results also show that HOX11L2 expression essentially occurs as a result of a 5q35 rearrangement, but is not associated with another identified T-ALL specific recurrent genetic abnormality, such as SIL-TAL fusion or HOX11 expression.

Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogénétique Hématologique study

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.

A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma.

Two types of structural alterations of the JAK2 kinase – point mutation and rearrangement following t(8;9) translocation – have been recently found in myeloproliferative disorders and acute leukaemias. We now report the characterisation of a t(8;9)(p22;p24) with PCM1-JAK2 gene fusion in a T-cell lymphoma. A 40-year-old man was referred to the haematological unit for cervical and axillar lymphadenopathy in September 1998. He presented with large peripheral lymphadenopathies in all areas; the ECOG score was 4. The leukocyte count, haemoglobin level and platelet count were normal as well as LDH. The computed tomography scan of thorax, abdomen and pelvis showed small retroperitoneal lymphadenopathies. The lymph-node biopsy showed infiltration with abnormal CD2þ , CD3þ , CD7þ , CD4 , CD5 , CD8 , CD1A low lymphocytes, with a high index of proliferation. Bone marrow (BM) aspiration and biopsy were normal. The diagnosis was lymphoblastic T lymphoma IIIBa. Induction chemotherapy based on acute lymphoblastic leukaemia (ALL) chemotherapy (association of vincristin, anthracyclin, cyclophosphamide and steroid) allowed complete remission (CR). The patient received four courses of consolidation chemotherapy, 18-gray central nervous system radiotherapy and 2 year-maintenance chemotherapy. Peripheral blood stem cells were collected and stored after chemotherapy and G-CSF.

NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia

The recurrent translocation t(8;16)(p11;p13) is found in about 6.5% of acute myeloid leukemias (AMLs) of the M4/M5-FAB subtypes. These poor prognosis AMLs are associated with erythrophagocytosis by blast cells. The translocation results in the fusion of the MYST3 gene (also known as MOZ) on chromosome region 8p11 to the CREBBP gene (also known as CBP) on chromosome region 16p13.1, 2, 3 In the same type of AML, the t(10;16)(q22;p13) fuses MYST3-homolog MYST4 to CREBBP4 and the t(8;22)(p11;q13) fuses MYST3 to CREBBP-homolog EP300.5 MYST3, MYST4, CREBBP and EP300 encode transcriptional regulators and acetyltransferases. MYST3 is also fused to NCOA2 in the inv(8)(p11q13).6, 7 NCOA1/SRC1, NCOA2/TIF2 and NCOA3 are paralogous genes encoding transcription coactivators of the p160 family.8 Some rearrangements involving NCOA genes and MYST3 or MYST4 genes have not been reported yet, but have been suspected or predicted on the basis of homology relations.4 We report here a new type of translocation, t(8;20)(p11;q13), which occurs in an M5-AML and fuses MYST3 to NCOA3.

Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome

Background Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. Design and Methods One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20×109/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. Results Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%–38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. Conclusions Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.

Five new cases of juvenile renal cell carcinoma with translocations involving Xp11.2: a cytogenetic and morphologic study

Two cases of renal cell carcinoma (RCC) carrying a t(X;1)(p11.2;q21) in a 12-year-old boy and a 14 year-old girl, two cases with a t(X;1)(p11.2;p34) in a 9-year-old boy and a 31-year-old woman, and one case with a t(X;17)(p11.2;q25) in a 15-year-old boy are reported. Two are likely papillary RCC, with clear or slightly eosinophilic cells, and two to a clear cell RCC; one shows a mixture of papillary and clear cell RCC architecture. Renal cell carcinomas with translocations involving Xp11.2 form a specific entity characterized by subtle pathologic features and younger age of occurrence, especially for those with the t(X;17).

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases

The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.

Mechanisms of genesis of variant translocation in chronic myeloid leukemia are not correlated with ABL1 or BCR deletion status or response to imatinib therapy

Many published studies have indicated that various mechanisms could be involved in the genesis of variant chronic myelogeneous leukemia (CML) translocations. These are mainly one-step or two-step mechanisms, associated or not with deletions adjacent to the translocation junction on der(9) or der(22) chromosomes (or both). Based on the mechanism of genesis, it has been suggested that the complexity may affect the occurrence of ABL1 and BCR deletions (either or both), or may be associated with the CML disease course, and thus could determine the response to imatinib therapy. Through a retrospective molecular cytogenetic study of 41 CML patients with variant Philadelphia chromosome (Ph), we explored the genesis of these variant rearrangements and analyzed the correlation with deletion status and imatinib efficiency. Our results confirmed that the one-step mechanism is the most frequent, evidenced in 30 of 41 patients (73%); 3 patients demonstrated other more complex multistep events and 8 patients (19.5%) harbored ABL1 or BCR deletions that are not significantly associated with the complexity of translocation genesis. We also found no association between one-step, two-step, or multistep mechanisms and the response to imatinib therapy.