Late Appearance of t(9;22) at Relapse, in an Adolescent with an Homozygous 9p Deletion T-ALL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4458-4458
Author(s):  
Vassilios Papadakis ◽  
Stefanos Papadhimitriou ◽  
Anna Paisiou ◽  
Chrysoula Belesi ◽  
Agapi Parcharidou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Philadelphia Chromosome ◽  
Great Majority ◽  
Homozygous Deletion ◽  
Chromosome 9 ◽  
Complex Karyotype ◽  
Cell Type ◽  
Clone Evolution ◽  
Underlying Pathogenesis

Abstract T-ALL has increasing incidence during adolescence and it is rarely associated with Philadelphia chromosome positivity. Moreover, extremely rare is the event of Philadelphia chromosome negativity at diagnosis and leukemia clone evolution with t(9;22) at relapse. Such a patient is being described and relevant issues are being raised. A 14 year old boy was diagnosed with leukemia due to malaise and ecchymoses. CBC revealed: WBC 170 k/uL (80% blasts), Hb 13.1 gr/dL, Ht 37.7% and PLT of 26 k/uL. Bone marrow confirmed the diagnosis of ALL (L2 morphology). Bone marrow flow cytometry depicted a T II ALL by EGIL classification (Tdt 54%, cCD3 99%, CD7 96%, CD2 96%, CD4 0%, CD8 2%, CD5 75%, TCRαβ 0%, CD1α 0%, sCD3 31%). Karyotype with G-banding, technically failed. By PCR, blasts were negative for TEL-AML1, E2A-PBXand MLL-AF4 while RNA coding for proteins p190 and p210 was also negative. Additionally, the 9 chromosome was evaluated by FISH technique (centromere and 9p21 areas/genes p16/p14 and p15- Vysis) and an homozygous deletion of 9p16 area was detected in the great majority of the blasts tested. The patient was treated according to the ALL-BFM-95 protocol and proved to be a poor prednisone responder, with residual disease detected on day +15 bone marrow and remission on day +33. He proceeded to the High Risk arm of the protocol. Thirteen months from diagnosis and 5 months on maintenance treatment, the patient suffered a bone marrow relapse. CBC revealed: WBC 30 k/uL (25% blasts), Hb 13.8 gr/dL, Ht 40.9 % and PLT of 201 k/uL. Bone marrow confirmed the relapse (L2 blast morphology) with a more mature T-cell type (cCD/TdT coexpression, with CD3 87% and TCRαβ 53.3% expression). Five of 25 metaphases revealed the following complex karyotype: 46,XY,del(6)(q21),?del(7)(q36), -9, t(9;22)(q34;q11),+mar1. By FISH , monosomy of 9 chromosome was not proved , while homozygous deletion of 9p16 area was again documented and t(9;22) was clearly evident. By PCR, there was no detection of RNA coding for proteins p190 and p210 with standard commercially available probes. The patient is treated with a fludarabine based regimen and imatinib, with the prospective of stem cell transplantation. In conclusion, at diagnosis, T-ALL without t(9;22) but with an homozygous deletion of chromosome 9, was documented. At relapse, there is clone evolution with a more mature T-origin blast detection of a complex karyotype with t(9;22). Ph+ T-ALL is rare, as well as rare is the event of ALL clone evolution, with emergence of Ph+ at relapse. This patient’s data are being completed and there is prospective of further illuminating the underlying pathogenesis. Chromosome 9 deletions are under investigation for contributing in genetic instability. Homozygous 9p16 deletion of ALL blasts at diagnosis and relapse might play a key role in these events.

scholarly journals Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

2020 ◽  
Vol 21 (16) ◽  
pp. 5776 ◽  
Author(s):  
Lukasz Komorowski ◽  
Klaudyna Fidyt ◽  
Elżbieta Patkowska ◽  
Malgorzata Firczuk
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Great Majority ◽  
Metabolic Reprogramming ◽  
Chromosome 9 ◽  
Treatment Protocols ◽  
Resistant Disease

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

scholarly journals Detection by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1735-1741 ◽  
Author(s):  
W Lange ◽  
DS Snyder ◽  
R Castro ◽  
JJ Rossi ◽  
KG Blume
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Enzymatic Amplification ◽  
Polymerase Chain ◽  
Marrow Cells

Abstract The Philadelphia chromosome of chronic myelogenous leukemia (CML) patients is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. A new bcr- abl mRNA is expressed in these cases. We have developed a modified polymerase chain reaction (PCR) for the detection of this mRNA. The method is extremely sensitive, reliable, and relatively fast. The analysis of peripheral blood or bone marrow cells from CML patients treated with chemotherapy shows that the two possible mRNAs are expressed in various combinations. Our results show that even after myeloablative therapy for bone marrow transplantation bcr-abl mRNAs are still expressed. Further studies, however, are necessary to determine the clinical relevance of a small number of persisting cells expressing the bcr-abl mRNA.

A Translocation (9;22)(p24;q11.2) In a Patient With CML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5184-5184
Author(s):  
Daniele Costa Abreu ◽  
Ana Paula Castilho, Bachelor ◽  
Vivian Dionísio Niewiadonski, Bachelor ◽  
Mauricio Drummond ◽  
Nelson Gaburo
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Medical Information ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Chromosome Analysis ◽  
Chromosome 9 ◽  
Fish Analysis ◽  
Ph Chromosome

Abstract Introduction In January 2013 was received in our lab service a bone marrow sample for cytogenetic analysis. The 61 years old female patient presents an elevated white blood cell count (118,000 x10³/mm³) and clinical diagnosis as Chronic Myeloid Leukemia (CML). According the medical information the treatment began with hydroxyurea 3g daily and allopurinol 300mg daily. Methods We proceeded with cytogenetic examination of the patient’s bone marrow aspirate by conventional G-banding analysis performed on unstimulated short-term cultures (24 hrs). FISH for BCR/ABL translocation was tested using a dual fusion dual color probe. Because of the sample stability we were unable to performed RT-PCR test. Results Chromosome analysis showed the translocation (9;22)(p24;q11.2) as a sole abnormality in 100% (20/20) of analyzed metaphases. Chronic myeloid leukemia presents as a specific chromosomal abnormality the Philadelphia chromosome, t(9;22)(q34;q11) which is different from the results obtained where the region of translocation of chromosome 9 was p24 instead of the classic q34. This result suggests it is BCR/JACK2 translocation. The FISH analysis showed the presence of a complex Ph chromosome: ABL con BCRx1 (one fusion) and BCRx2;ABLx2. Conclusion The patient took imatinib without answer. She is still in clinical monitoring with persistent hyperleucocytosis and the treatment is following with hydroxyurea 500mg daily and Interferon 5000 UI three times a week. Further molecular and cytogenetic tests will be performed in a second sample to contribute with evaluation of disease progression and monitoring treatment response. Disclosures: No relevant conflicts of interest to declare.

BCR-ABL Is Not an Immunodominant Antigen in CML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2881-2881
Author(s):  
Frank Grünebach ◽  
Valbona Mirakaj ◽  
Martin R. Müller ◽  
Tim Brümmendorf ◽  
Peter Brossart
Keyword(s):  
Bone Marrow ◽  
T Lymphocytes ◽  
Philadelphia Chromosome ◽  
Chimeric Protein ◽  
Genetically Engineered ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Specific Ctls

Abstract Chronic myelogenous leukemia (CML) is a myeloproliferative disorder, which originates from pluripotent hematopoietic bone marrow progenitor cells. It is characterized by excessive proliferation of the granulopoiesis in the bone marrow. In approximately 90% of the patients with CML the Philadelphia chromosome (Ph) is the characteristic cytogenetic hallmark. The Ph is a shortened chromosome 22, which arises from a acquired reciprocal translocation between chromosome 9 and 22 (t(9;22) (q34;q11)). This translocation fuses the bcr gene with part of the c-abl gene, which encodes a protein-tyrosine kinase. The chimeric bcr-abl oncogene is translated into a 210-kDa chimeric protein (p210) which exhibits constitutive ABL kinase activity. In the present study, we analysed the involvement of the BCR-ABL protein in the induction of antigen-specific cytotoxic T lymphocytes (CTLs) in order to develop an immunotherapeutic approach targeting this neo-antigen in patients with CML. To accomplish this, we generated dendritic cells (DCs) in vitro and electroporated them with various sources of RNA harbouring the chimeric bcr-abl transcript. These genetically engineered DCs where used as antigen presenting cells (APCs) for the in vitro induction of CTLs. By applying this approach we found that the CTLs induced by DCs transfected with RNA extracted from bcr-abl-positive K-562 cells or CML blasts do not recognize epitopes derived from the chimeric BCR-ABL fusion protein. In contrast, they were able to lyse autologous DCs electroporated with RNA isolated from patients with acute myeloid leukemia (AML), indicating that antigens shared among these malignant cells are involved and recognized by these CTLs. However, we successfully generated BCR-ABL-specific CTLs by DCs electroporated with in vitro transcribed bcr-abl-RNA. In patients with CML in complete cytogenetic remission during IFN-α treatment there was some reactivity against BCR-ABL in IFN-γ ELISPOT assays, which was weaker as compared to proteinase 3 (PR3)- or Prame-directed responses supporting the observations obtained in healthy donors. In summary, BCR-ABL is processed and presented by Ph+ cells but is not the immunodominat antigen that induces CD8+ T lymphocytes in competition with other tumor-associated antigens. Nevertheless, APCs transfected with pure bcr-abl-IVT in vitro are capable of inducing BCR-ABL specific CTLs that efficiently lyse Ph+ target cells.

Minimal Residual Disease in Adults with Advanced Relapsed Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Treated with Marqibo® (vinCRIStine sulfate LIPOSOME injection)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4805-4805
Author(s):  
Olivia R. Deitcher ◽  
Stuart L. Goldberg ◽  
Wendy Stock ◽  
Gary J. Schiller ◽  
John Lister ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Response Duration ◽  
Bone Marrow Blast ◽  
Molecular Remission ◽  
Vincristine Sulfate ◽  
Minimal Residual

Abstract Abstract 4805 Minimal residual disease (MRD) testing in acute lymphoblastic leukemia (ALL) has been primarily used in the frontline treatment setting following achievement of morphologic remission where absence of detectable disease (molecular remission) may predict for a more favorable outcome. Potential utility of post-induction MRD testing in the advanced, relapsed/refractory adult Philadelphia chromosome (Ph) negative ALL setting has not been reported. We assessed MRD in the pivotal Phase 2 RALLY Study (HBS407, NCT00495079) of weekly high-dose (2.25 mg/m2 without any dose cap) vincristine sulfate liposome injection (VSLI, Marqibo®) monotherapy in 65 patients with either B- or T-cell lineage, Ph-negative ALL in 2nd or greater relapse or that had progressed following 2 or more lines of prior anti-leukemia therapy. All patients were heavily pretreated, all had received prior standard vincristine (VCR), 48% had undergone a prior hematopoietic cell transplant, and 43% were refractory to their immediate prior line of therapy. The median bone marrow blast percentage at presentation was 82%. Complete response (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 13 (20%) patients based on principal investigator (PI) assessment (predefined primary endpoint) and in 11 (17%) patients as assessed by an independent response review committee (IRRC). Two patients assessed as CR/CRi by a PI were classified as bone marrow blast (BMB) responders (morphologic remission lacking neutrophil and platelet count recovery) by the IRRC. MRD data from the first bone marrow demonstrating VSLI-induced CR/CRi based on site-specific flow cytometry methodology were available in 12 of the 13 CR/CRi patients. Molecular remission was confirmed in 8 of 12 (67%) patients. Response and VSLI treatment details for the MRD-negative and MRD-positive groups are provided in the table MRD Negative N = 8 MRD Positive N = 4 PI Response Assessment CR 5 1 CRi 3 3 BMB Responder 0 0 IRRC Assessment CR 6 1 CRi 0 3 BMB Responder 2 0 Response Duration, Median (Range) 140 days (32–162) 87 days (35–210) Overall Survival, Median (Range) 230 days (121–321) 203 days (71–327) VSLI Doses, Median (Range) 9 (4–18) 5 (4–10) VSLI Exposure (mg of VCR), Median (Range) 35.9 (17.4–58.6) 20.1 (15.8–33.4) Most (83%) patients who achieved a CR were MRD-negative. Half of the CRi patients, based on PI assessment, were MRD-negative. Both of the BMB responders, based on IRRC assessment, were MRD-negative. Median response duration, overall survival, number of VSLI doses, and cumulative VSLI dose expressed as milligrams of VCR were larger in patients who were MRD-negative. VSLI monotherapy administered as a third-, fourth-, or fifth-line therapy in adults with advanced, relapsed/refractory Ph-negative ALL was able to induce morphologic remission in 13 of 65 (20%) of patients and molecular remission in 8 of 12 (67%) evaluable morphologic remissions. MRD negativity may result from greater VSLI exposure and may be associated with more favorable response durations. MRD assessment may help to determine remission status particularly in patients with morphologic remission and incomplete recovery of either (i.e., CRi) or both (i.e., BMB Response) the peripheral blood platelet count and neutrophil count secondary to extensive prior myelotoxic therapy. Disclosures: Goldberg: Eisai: Speakers Bureau. Silverman:Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

scholarly journals Quantification of the breakpoint cluster region rearrangement for clinical monitoring in Philadelphia chromosome-positive chronic myeloid leukemia

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2705-2710 ◽  
Author(s):  
CF Verschraegen ◽  
M Talpaz ◽  
CF Hirsch-Ginsberg ◽  
R Pherwani ◽  
MB Rios ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Philadelphia Chromosome ◽  
Disease Suppression ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Molecular Studies

The purpose of this report was to evaluate scintigraphy analysis of Southern blot hybridization as a method to quantify the breakpoint cluster region (BCR) rearrangement of Philadelphia chromosome (Ph)+ chronic myelogenous leukemia (CML). Cytogenetic and molecular studies performed simultaneously on 474 bone marrow and/or blood samples from 300 patients treated with alpha-interferon-based therapy were compared. Molecular results were expressed as the percentage of rearranged BCR bands versus the total scintigraphic signal. The percentage of Ph+ metaphases was calculated on 25 metaphases. The results of molecular studies obtained on both peripheral blood and bone marrow samples were identical. The rank correlation between the BCR quantification and the percentage of Ph positivity in 465 samples was excellent (r = .78). However, of 99 samples with a normal karyotype, 24% had a BCR rearrangement. Of 86 samples with no BCR rearrangement, 13% showed a Ph chromosome. Of 49 samples with partial cytogenetic remission (Ph+ metaphases, 1% to 34%), 23% had no BCR rearrangement. In samples with a minor or no cytogenetic response (Ph+ metaphases, > 34%), BCR analysis overestimated the degree of response in 73 of 326 samples (22%). Nevertheless, survival analysis by BCR quantification level showed statistically better outcome for patients in complete or partial molecular response (P < .01). Molecular quantification of BCR was useful in monitoring the course of Ph+ CML. This method, which can be used on peripheral blood, detected residual disease not shown by cytogenetic analysis and was prognostically relevant as a measure of disease suppression.

scholarly journals Discrete clusters of hematopoietic cells in the marrow cavity of man after bone marrow transplantation

Blood ◽  
1977 ◽  
Vol 50 (4) ◽  
pp. 709-712 ◽  
Author(s):  
MJ Cline ◽  
RP Gale ◽  
DW Golde
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Leukemia ◽  
Marrow Transplantation ◽  
Hematopoietic Cells ◽  
Great Majority ◽  
Cell Types ◽  
Cell Type ◽  
Marrow Cavity ◽  
Single Cell Type

Abstract Discrete aggregates of hematopoietic cells were observed in the bone marrows of patients with aplastic anemia or acute leukemia 14 days after marrow transplantation. The great majority of such colonies were of a single cell type, and less than 3% contained two or more cell types. Erythroid, myeloid, and undifferentiated hematopoietic colonies were approximately equal in frequency.

INK4 Locus Deletion in Childhood Acute Lymphoblastic Leukemia (ChALL)-a Preliminary Clinical Evaluation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4858-4858
Author(s):  
Anna Paisiou ◽  
Stefanos I Papadhimitriou ◽  
Nikolaos Tsagarakis ◽  
Vassilios Papadakis ◽  
Nektaria Kentrou ◽  
...  
Keyword(s):  
T Cell ◽  
Prognostic Factor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Demographic Data ◽  
Homozygous Deletion ◽  
Chromosome 9 ◽  
Positive Finding ◽  
Medium Risk

Abstract Introduction: Deletions of the INK4 locus (on chromosomal region 9p21) are common in chALL. p16/14 and p15 genes lost with INK4 deletion are tumor suppressors, with a well-documented role in regulating cell cycle and chemosensitivity and in promoting apoptosis in vitro. However, the clinical significance of INK4 deletions remains unclear. Patients & Methods: The study included 78 children (49 boys and 29 girls) with ALL (medium age: 3,12, range:0,7 to 16,5 ). The disease was of B- and T-cell origin in 70 and 8 cases, respectively. INK4 deletion was investigated by interphase FISH on the diagnostic bone marrow samples and the result was correlated with the patients’ demographic data, biological and clinical parameters, and disease outcome. All patients were treated according to the ALL-BFM-95 protocol and followed-up for 11–105 (medium 41) months. Results: INK4 locus deletion was found in 24 cases (30.8%). The loss was hemizygous in 15 (19.2%) and homozygous in 9 cases (11.5%). A positive finding was strongly associated with disease of T-cell origin (p=0.008). Apart from a weak correlation between INK4 deletion and advanced age (p=0.068), there was no association with sex, initial leucocytosis level, cytogenetic category, risk group grade according to the ALL-BFM- 95 criteria or the presence of residual disease at days 15 and 33. Nevertheless, INK4 homozygous deletion was significantly associated with disease-free (p=0.004) and overall survival (p=0.002), while the respective associations for an hemizygous deletions were found insignificant (p=0.137 and p=0.131). Conclusions: The findings from this cohort of children suggest that INK4 homozygous deletion is an unfavorable prognostic factor in chALL, even for cases in which an aggressive course cannot be predicted by the conventional risk estimating criteria. Unclear results with regard to hemizygous deletion may be attributed to the functional state of remaining p16/p14 and p15 genes on the non-deleted chromosome 9. The study of a greater group of patients and the extension of the follow-up period will hopefully clarify whether INK4 deletion is an independent prognostic factor and whether it could be incorporated in risk evaluation guidelines, especially for cases which would otherwise be treated as chALL of standard or medium risk.

BCR/ABL Fusion Gene On Constitutional Der(14;22) Roberstsonian Translocation in a Case of Chronic Myeloid Leukemia with Masked Philadelphia Chromosome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4822-4822
Author(s):  
Pablo Lopez ◽  
Daniela Infante ◽  
Isabel Moro ◽  
Victoria Elizondo ◽  
Gerardo Romanelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Robertsonian Translocation ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Ph Chromosome ◽  
One Step

Abstract Abstract 4822 Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome (Ph) observed in more than 90% of patients with CML as a result of t(9;22)(q34;q11), leading to the formation of the BCR/ABL chimeric gene. The remaining 5–10% of CML cases exhibit a variant Ph translocation generally involving a third or even a fourth chromosome in addition to chromosome 9 and 22, potentially leading to masked Ph chromosome or reveal cryptic translocations that remains undetected under conventional cytogenetic analysis. These chromosome rearrangements can be disclosed by means of fluorescence in situhybridization (FISH) or polymerase chain reaction (PCR) procedures. A very few Ph positive CML cases were reported with constitutional robertsonian translocations, i.e. translocation between two acrocentric chromomosomes (13–15, 21–22), with breakpoints in the short arms, leading to a dicentric chromosome and thus to 45 instead of 46 chromosomes Case Report. 42 year-old woman presenting with asthenia. Physical examination: Grade 1 splenomegaly. Peripheral blood count showed: hemoglobin concentration 117g/L, platelet count: 329×109/L and white blood cell count (WBC): 199×109/L. Peripheral blood smear: myelemia exhibiting 3% of myeloid blasts. Cytogenetic analysis by G-banding performed on bone marrow metaphase cells afforded the following karyotype: 45, XX, der(14;22)(q10;q10)c?, t(9;22;11)(q34;q11;q13) [20]. The analysis of the BCR-ABLfusion gene according to standard protocols detected the presence of the b3a2 isoform. FISH studies using dual color dual fusion probes in metaphases showed a 1F2G2R signal pattern. We detect a normal ABL signal on chromosome 9 and BCR signal on chromosome 22; the fusion signal was present on the der(14;22);extra-signals BCR and ABL with reduced intensities were present on der(11) and der(9) respectively: ish der(9)(ABLdim+), der(11)(BCRdim+), der(14;22)(BCR+,ABL+) [10]. FISH analysis on interphase nuclei (n=200) presented the same signal pattern. Nuc ish (ABL, BCRx3)(BCR con ABL x1) [200]. Chromosome analysis of bone marrow cells after six months of Imatinib therapy showed the following karyotype: 45, XX, der(14;22)(q10;q10)c [20] thus demonstrating complete cytogenetic remission and that der(14;22) is a robertsonian constitutional abnormality that could be inherited and thus necessitate a familial genetic councelling to inform about the familial risk of congenital malformations and miscarriage. Discussion. To explain the formation of variant chromosome Ph translocations one-step, two-step and multi-step mechanisms have been proposed. In our case complex translocations involving four chromosomes and the participation of two acrocentric chromosomes, led to the hypothesis of the presence of a constitutional or acquired Robertsonian translocation. Karyotype analysis six months after treatment confirmed the presence of a constitutional Robertsonian translocation. According to the FISH pattern, this variant Ph chromosome was formed in one step. The occurrence of Philadelphia positive CML in a patient with a constitutional Robertsonian translocation is probably coincidental. The role of constitutional chromosomes abnormalities in hematologic malignancies is well known in Down syndrome patients and in chromosome breakage syndromes such as Fanconi anemia. In the literature, only one case of CML patients with Robertsonian t(14;22) have been described. To our knowledge this is the first report showing a Robertsonian t(14;22) in a variant Ph involving four chromosomes and exhibiting the fusion FISH signal in a derivative chromosome 14, with masked Ph. Disclosures: No relevant conflicts of interest to declare.

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