Angela Scalise

Exploring polycythaemia vera with fluorescence in situ hybridization: additional cryptic 9p is the most frequent abnormality detected*

Summary. Between 1986 and 2001, 220 patients with polycythaemia vera (PV) were studied using conventional cytogenetics. Of 204 evaluable patients, 52 (25·4%) had clonal abnormalities. The recurrent chromosomal rearrangements were those of chromosome 9 (21·1%), del(20q) (19·2%), trisomy 8 (19·2%), rearrangements of 13q (13·4%), abnormalities of 1q (11·5%), and of chromosomes 5 and 7 (9·6%). Subsequent analysis of 32 patients, performed at follow‐up of up to 14·8 years, revealed new clonal abnormalities in five patients and the disappearance of an abnormal clone in four. Eleven patients remained normal up to 11·5 years and seven patients maintained an abnormality for over 10 years. Fifty‐three patients were studied retrospectively using interphase fluorescence in situ hybridization (I‐FISH), utilizing probes for centromere enumeration of chromosomes 8 and 9, and for 13q14 and 20q12 loci. Conventional cytogenetics demonstrated clonal chromosome abnormalities in 23% of these 53 patients. The addition of I‐FISH increased the detection of abnormalities to 29% and permitted clarification of chromosome 9 rearrangements in an additional 5·6% of patients. FISH uncovered rearrangements of chromosome 9 in 53% of patients with an abnormal FISH pattern, which represented the most frequent genomic alteration in this series.

Clonal chromosomal abnormalities in Fanconi's anaemia: what do they really mean?

Summary. Patients with Fanconis anaemia (FA) have aplastic anaemia, leukaemia, myelodysplasia and tumours. Since leukaemia has a very poor prognosis, it is desirable to identify high‐risk patients. To determine the significance of clonal marrow chromosomal abnormalities we began a prospective study in 17 patients: five were normal, eight aplastic, and four myelodysplastic. Three of 11 with adequate cytogenetics had transient abnormal clones. None had leukaemia at 3–24 months. Changing cytogenetic patterns may not be related to leukaemic evolution in patients with a DNA repair defect.

del(5q) in acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype.

We report three patients with acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype who had del(5q). In the first patient, the del(5q) was the sole abnormality; in the second patient, the del(5q) was interpreted as subclonal evolutionary event; while in the third patient, the rearrangement was transiently present 7 months following the diagnosis of Ph-positive ALL, while the patient was in clinical remission. Review of the literature indicates that del(5q) is rare in ALL. In contrast to its presence in AML, del(5q) in ALL is not an adverse prognostic indicator, and it appears to be more frequent in children.

Jumping translocations of the long arms of chromosome 1 in myeloid malignancies is associated with a high risk of transformation to acute myeloid leukaemia

transplantation. Bone Marrow Transplantation, 43, 429–431. Kyttälä, S., Habermann, I., Minami, T., Ehninger, G. & Kiani, A. (2009) Regulation of Down Syndrome Critical Region 1 expression by Nuclear Factor of activated T cells in megakaryocytes. British Journal of Haematology, 144, 395–408. Malinge, S., Izraeli, S. & Crispino, J.D. (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood, 113, 2619–2628. O’Connell, R.M., Rao, D.S., Chaudhuri, A.A., Boldin, M.P., Taganov, K.D., Nicoll, J., Paquette, R.L. & Baltimore, D. (2008) Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. Journal of Experimental Medicine, 205, 585–594. Ruiz-Argüelles, G.J., Ruiz-Argüelles, A. & Garcés-Eisele, J. (2007) Donor cell leukaemia: a critical review. Leukaemia & Lymphoma, 48, 25–38. Salek-Ardakani, S., Smooha, G., de Boer, J., Sebire, N.J., Morrow, M., Rainis, L., Lee, S., Williams, O., Izraeli, S. & Brady, H.J. (2009) ERG is a megakaryocytic oncogene. Cancer Research, 69, 4665– 4673. Sevilla, J., Querol, S., Molines, A., González-Vicent, M., Balas, A., Carrió, A., Estella, J., Angel Dı́az, M. & Madero, L. (2006) Transient donor cell derived myelodysplastic syndrome with monosomy 7 after unrelated cord blood transplantation. European Journal of Haematology, 77, 259–263.

Evidence for the embryonic origin of partial chromosome 7 deletion in monozygotic twins with juvenile chronic myelogenous leukemia.

During donor evaluation for allogeneic bone marrow transplantation (BMT) of a 28-month-old child with juvenile chronic myelogeneous leukemia (JCML) with 46,XY,−7,+mar karyotype, the potential donor twin brother was found to be thrombocytopenic. Subsequent genotype analysis determined monozygosity with 98% probability. Bone marrow analysis of the twin brother revealed the same 46,XY,−7,+mar karyotype and a diagnosis of JCML was made. Metaphase FISH studies documented that mar chromosome in both twins contains the pericentromeric region of chromosome 7 and thus both twins had a partial monosomy of chromosome 7. A possible embryonic origin of del(7) is proposed.

Disparate lympho-erythroid donor to recipient chimaerism in a β°-thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment

A 4‐year‐old girl with transfusion‐dependent β°‐thalassaemia received an HLA‐identical bone marrow transplant (BMT) from her β°‐thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post‐BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU‐E) was analysed. On days 1000 and 1130 post‐BMT, 79% and 77% of colonies, respectively, synthesized β‐globin and therefore were of donor origin.

The value of interphase fluorescence in situ hybridization in the study of patients with lymphoproliferative disorders: further evidence for a higher sensitivity of detecting chromosomes 7 and 8 aneuploidy.

Dual-color interphase fluorescence in situ hybridization (I-FISH) for chromosomes 7 and 8 was studied retrospectively on 32 patients with suspected lymphoid disorders, and the results were compared with standard cytogenetics. One of 29 (3.4%) patients with lymphoid malignancy showed cytogenetically detectable aneuploidy for chromosomes 7 and 8. In an additional 5 patients (17.2%), I-FISH unmasked chromosomal loss and gain that were not detected by standard metaphase analysis. This represents 19% of the 21 studied patients with acute lymphoblastic leukemia (ALL). These findings indicate that aneuploidies for chromosomes 7 and 8 are underreported in ALL and further demonstrate higher sensitivity of I-FISH for detecting numerical chromosomal rearrangements in leukemic cells.

Duplication and triplication of der(21)t(8;21)(q22;q22) in acute myeloid leukemia.

We report on two patients with complicons resulting in duplication der(21)t(8;21)(q22;q22), triplication in the form of isochromosome of der(21)t(8;21), and four copies of ETO-AML1 fusion. Duplication of der(21) was present at diagnosis as a minor cell population in one patient, while the presence of isoderivative (21)t(8;21) characterized the relapse cells of the second patient. Due to the rarity of these cases, literature search of other reported cases of complicons may be taken as evidence that duplication and triplication of ETO-AML1 may be a poor prognostic indicator, regardless of whether it is present at diagnosis or relapse.

Chromosome 21 rearrangement in acute biphenotypic leukemia

A patient with myelodysplastic syndrome (MDS) and a 47,XY,+21 karyotype at diagnosis, was documented to have a clonal chromosome 21 rearrangement, i(21q), four months before transformation to acute biphenotypic leukemia. For 4 months after transformation, isochromosome 21 persisted while the patient was receiving treatment with zidovudine. Vitamin D3 was added to zidovudine for an additional month, during which time the trisomy 21 clone reappeared as the predominant cell population. The unique aspects of this patient are the atypical evolution of chromosome 21, the transformation to biphenotypic leukemia, and the occurrence of i(21q) associated with biphenotypic leukemia evolving from an MDS.

Cytogenetically Normal Acute Myeloid Leukemia with a Novel KIT Mutation in Exon 11 G565V Developing a Sole Trisomy 13 at Relapse: A Clinical Dilemma

We describe a patient with acute myeloid leukemia (AML) who had a normal karyotype at diagnosis and was negative for NPM1 and FLT3 mutations, but had a KIT G565V mutation in exon 11. This has not been described previously in AML. The patient received induction and consolidation chemotherapy and was in hematologic remission for 351 days when deletion 7q was cytogenetically detected in 8% of the bone marrow cells. After an initial treatment of azacitidine followed by decitabine, an unrelated trisomy 13 clone was identified, followed by subclonal rearrangement of ETV6. The patient underwent reinduction with high-dose cytarabine and mitoxantrone followed by voluntary-unrelated-donor allogeneic stem cell transplantation with a reduced-intensity conditioning. As of writing, the patient is in complete hematologic and cytogenetic remission with 100% donor cell engraftment.