Ph Chromosome-positive Chronic Myeloid Leukemia Research Articles

Environmental and occupational factors associated with chronic myeloid leukemia: a case-control study

BackgroundThe relationship between chronic myeloid leukemia (CML) and a broad range of exposures to occupational and environmental factors known to cause leukemia in general is limited. CML is by and large incurable and treatment is just palliative and life prolonging, with high case fatality rate, even in the best centers. Furthermore treatment is very expensive. Identification of leukemogenic factors is therefore important if this can lead to simple public health interventions.ObjectiveThe objective was to determine key environmental and occupational exposure factors that may be associated with CML.MethodsThis was a case-control study involving CML cases enrolled in Glivec International Patient Assistance Program (GIPAP) clinics at the Nairobi Hospital and Aga Khan University Hospital and two control groups for each case, matched for age and sex: a family- and hospital-based control, was carried out. One hundred and eight cases with ageand-gender-matched family- and hospital-based controls were recruited and a standard questionnaire was administered. Individual data on demographics, occupation, environment, and exposures to benzene and farm organochemical products were obtained. Clinical examination was carried out in control subjects. Statistical analysis was done using bivariate and multivariate analysis to look for associations between exposure factors and CML.ResultsThe median age at diagnosis of CML cases was 41.32 years with an age range of 8–81 years and a male to female ratio of 1.7:1. Most of our cases were concentrated in or around Nairobi. There was no significant correlation found for exposure to benzene or pesticides. Long duration of exposure to pesticides in the family control group was significantly associated (t-test, P = 0.017) with risk of CML.ConclusionsAssociations between exposures to organic solvents like pesticides and CML were indicated but were not entirely consistent, although no associations with benzene products were found. Nevertheless, for almost all cases of Ph chromosome-positive CML, other explanations must be sought for.

A novel cytogenetic abnormality r(7)(::p11.2->q36.3::) in a Philadelphia-positive chronic myeloid leukemia case

The so-calledPhiladelphia(Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. It results in juxtaposition of the 5' part of the BCR gene on chromosome 22 and the 3' part of the ABL1 gene on chromosome 9. An additional acquired monosomy 7 or deletion of 7q is associated with poor prognosis in a variety of myeloid disorders. Here we report a novel Ph chromosome positive CML case with a ring chromosome 7 [r(7)]. Immunophenotyping was compatible with CML, although 4.5% of total leucocytes appeared like acute myelogeneous leukemia (AML) subtype M2. The r(7) was characterized in detail by array-proven multicolor banding (aMCB), the latter being of enormous significance to characterize breakpoint regions in detail. Underlying mechanisms and prognostic are discussed, as ring chromosomes are rare cytogenetic abnormalities in hematopoietic malignancies.

A novel dic (17;18) (p13.1;q11.2) with loss of TP53 and BCR/ABL rearrangement in an Imatinib resistant chronic myeloid leukemia

BackgroundThe so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL gene on chromosome 9. Since the majority of CML cases are currently treated with Imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The T315I mutation within the abl-gene is the most frequent one associated with resistance to tyrosine kinase inhibitors.ResultsThis study evaluated a Ph chromosome positive CML case resistant to imatinib mesylate. A dic(17;18), loss of TP53 gene, co-expression of b2a2 and b3a2 fusions transcript and a T315I mutation were found.ConclusionsWe reported here a novel case of a Ph chromosome positive CML with a secondary abnormality [dic(17;18)], resulting to Glivec resistance but good response to nilotinib. The dic(17;18) might be a marker for poor prognosis in CML. Our finding indicated for an aggressive progression of the disease. The patient died under the treatment due to unknown reasons.

A rare chronic myeloid leukemia case with Philadelphia chromosome, BCR-ABL e13a3 transcript and complex translocation involving four different chromosomes

The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) patients. Around 5-10% of these patients show complex translocations involving other chromosomes in addition to and/or besides chromosomes 9 and 22. CML cases with fusion transcripts, such as e13a3, in which ABL exon 3 rather than exon 2 has fused to BCR, are extremely rare. Such reported cases with the e13a3 transcript showed the Ph chromosome on karyotype analysis. This study reported a rare Ph chromosome-positive CML case with new complex chromosomal aberrations and an e13a3 BCR-ABL transcript that has yet to be established. A four-chromosome translocation involving chromosomal regions 12p11.2, 19q13.3, 9q34.1 and 22q11.2, besides a trisomy 8 and a derivative chromosome 12, were identified using high resolution multicolor banding. Reverse transcription polymerase chain reaction products showed the presence of BCR-ABL fusion transcript e13a3, and this signifies the major BCR breakpoint. The significance of the observed rearrangements and their possible role in the progression of CML was investigated.

A rare case of chronic myeloid leukemia with secondary chromosomal changes including partial trisomy 17q21 to 17qter and partial monosomy of 16p13.3

BackgroundThe so-called Philadelphia (Ph) chromosome is present in almost all cases with chronic myeloid leukemia (CML). Around 5-10% of these patients show complex translocations involving other chromosomes in addition to and/or besides chromosomes 9 and 22. As nowadays most CML cases are treated with Imatinib, variant rearrangements have in general no specific prognostic significance, though events of therapy resistance remain to be studied.ResultsHere we report a Ph chromosome positive patient with hematological typical chronic phase CML. Untypically, an unbalanced complex rearrangement involving chromosomes 16 and 17 leading to a deletion of 16pter and partial trisomy of 17q21 to 17qter, was identified besides a trisomy 8 and an additional Ph chromosome in a part of malignant cells.ConclusionHere a novel and cytogenetically unique case of a Ph chromosome positive CML clinically in chronic phase is reported, having complex secondary chromosomal aberrations. Thus, CML patients with complex chromosomal changes are nonetheless treatable by Imatinib.

Plasmablastic crisis of Philadelphia chromosome-positive chronic myeloid leukemia

Dear Editor, The cytogenetic hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), the consequence of the reciprocal translocation t(9;22)(q34;q11.2) that results in the BCR-ABL1 fusion gene, located in the Ph chromosome [1]. The natural history of untreated CML is an initial indolent chronic phase which is followed by a blast phase either suddenly or through an accelerated phase. Blast crisis may be diagnosed when blast cells are ≥20% of the peripheral blood WBC or the nucleated cells of the bone marrow or when there is an extramedullary blast proliferation [1, 2]. In approximately 70% of cases the blast lineage is myeloid while in 20–30% of cases the blasts are lymphoblasts [1, 2]. Progression is usually associated with clonal evolution, and at the time of transformation to blast crisis, 80% of patients demonstrate cytogenetic changes in addition to the Ph chromosome such as an extra Ph chromosome, +8, i(17q), +19, t(3;21)(q26;q22), and very rarely t(7;11)(p15;p15) [3]. Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy which is characterized by circulating plasma cells >2×10/l in peripheral blood or by a plasmatocytosis >20% of blood leukocytes and confers a poor prognosis. It originates as a primary disease or as a secondary leukemic transformation of multiple myeloma [4]. The most frequent features at diagnosis are asthenia, severe anemia, thrombocytopenia, splenomegaly, or hepatomegaly while CD38 and CD138 antigens are excellent plasma cell markers [5, 6]. In the majority of the cases, karyotypes are complex and hypodiploid or pseudodiploid. Common chromosome abnormalities are 14q32 translocations such as t(11;14)(q13;q32), t(4;14)(p16.3;q32), t(14;16)(q32;q23), deletions of the chromosomal regions 17p13, 13q, and 1p21, monosomies of chromosomes 13 and X (in women), trisomy 18, amplification of 1q21, and MYC rearrangements [4–7]. Here, we report for the first time a rapidly fatal case of a PCL crisis in a young patient with Ph chromosome-positive CML. The patient, a 43-year-old male with a 2-month history of persistent fatigue, weakness, and loss of weight was admitted to our department. On physical examination spleen was remarkably enlarged and routine complete blood count revealed leukocytosis with a WBC of 22× 10/l, anemia with a Hb of 7 gr/dl, and thrombocytopenia with platelet count of 30×10/l. Neither hypercalcemia nor proteinuria was observed. Blood smear showed 90% blasts with the appearance of plasma blasts (Fig. 1). Immunophenotyping of blast cells by flow cytometry showed CD45+ (79%), CD38+ (77%), CD34+ (56%), surface κ(−), surface λ(-), cytoplasmic κ+ (90%), cytoplasmic λ(−), and CD20 (−). The cytogenetic analysis of G-banded chromosomes in peripheral blood cells revealed two evolutionary clones, which were positive for Ph chromosome. The karyotype was described as: 46,XY,t(9;22)(q34;q11.2)[4]/32,XY,-2, -3,-4,-5,t(9;22)(q34;q11.2),-10,-11,-12,-13,-15,-16,-17,-18, -20,-22[16]. Unfortunately, the patient developed acute renal failure on the second day after admission and died 2 days later. K. N. Manola (*) Laboratory of Cytogenetics, National Center for Scientific Research (NCSR) “Demokritos”, 15310 Aghia Paraskevi, Athens, Greece e-mail: pmanola@ipta.demokritos.gr