|Year : 2017 | Volume
| Issue : 2 | Page : 381-383
Complexity of chromosomal rearrangements in Down syndrome leukemia
Bani Bandana Ganguly1, Nitin N Kadam2, Prakash K Mandal3
1 MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Navi Mumbai, Maharashtra, India
2 Department of Pediatrics, MGM Medical College and Hospital, Navi Mumbai, Maharashtra, India
3 Department of Hematology, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India
|Date of Web Publication||23-Jun-2017|
Bani Bandana Ganguly
MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Vashi Plot 35, Sector 3, Navi Mumbai - 400 703, Maharashtra
Source of Support: None, Conflict of Interest: None
Reports on imbalanced HSA21 gene expression and chromosomal rearrangements on leukemogenesis, drug sensitivity, and treatment outcome of leukemia in Down syndrome (DS) are limited. DS has been recognized as one of the most common leukemia-predisposing syndromes with unique clinical features, significant differences in treatment outcome and treatment-related toxicity profiles. Acute myeloid leukemia (AML), especially acute megakaryocytic leukemia, is reported with high cure rates presenting 80%–100% event-free survivals (EFSs); however, acute lymphoid leukemia indicates a worse prognosis in DS patients compared to non-DS children. Complex rearrangements are responsible for poor-to-very poor prognosis in all cases, irrespective of genetic predisposition or type of hematopoietic subunits affected. We report a 2-year-old female DS diagnosed with acute erythroleukemia (French–American–British: AML-M6) with highly complex chromosomal rearrangements in the bone marrow with 39 chromosomes. Parental consanguinity and genetic predisposition might be responsible for origin of multiple clones. Genetic instability and heterogeneity of complex clonal developments might cause poor prognosis. The case is a rare one with acute erythroleukemia in DS patient where too many rearrangements had masked identification of three 21s.
Keywords: Acute erythroleukemia, complex chromosomal rearrangements, Down syndrome, genetic mutations
|How to cite this article:|
Ganguly BB, Kadam NN, Mandal PK. Complexity of chromosomal rearrangements in Down syndrome leukemia. J Can Res Ther 2017;13:381-3
| > Introduction|| |
Down syndrome (DS), caused by HSA21, is the most prevalent chromosomal disorder resulted from meiotic (~97%)/mitotic (~3%) nondisjunction, mostly influenced by maternal age. The variable clinical/phenotypic expression and understanding of genotype–phenotype association of the key components along the HSA21 could not resolve the impact of unbalanced gene dosage. DS children have ~20-fold higher predisposition to leukemia. Transient myeloproliferative disorder (TMD) is often seen in DS newborns, which normally disappears spontaneously or eventually develops acute myeloid leukemia (AML) resulting in death by 3–4 years. A marked increase of the megakaryoblastic subtype (acute megakaryocytic leukemia [AMkL]: French–American–British [FAB]-M7) was seen in DS under 4 years although acute myeloblastic/myelomonocytic/monoblastic/lymphoblastic/erythro-leukemia has also been documented. Furthermore, DS patients frequently show a myelodysplastic phase preceding the development of AML.,
Involvement of RAS-pathway genes, which are described in number of neoplastic transformation and overexpression of RUNX1/AML1 gene, has been described in DS-acute leukemia (AL). However, chromosomal alterations, beyond trisomy 21, have sporadically been described in limited individual reports. We present wide spectrum of complex chromosomal rearrangements in DS developed AML-M6.
| > Case Report|| |
A 2-year-old DS female, born to consanguineous parents, was referred for bone marrow cytogenetics with a history of low-grade intermittent fever and packed red blood cell (RBC)/platelets transfusion due to pallor and single episode of melena/gum bleeding. The presence of black pigmentation on the forehead, hepatosplenomegaly, and few palpable lymph nodes directed a provisional diagnosis of AL.
Hemogram showed hemoglobin 5.4 g/dl, RBC 1.8 million/μL, white blood cell (WBC) 2900/μL, platelet 24000/μL, and hypochromic RBCs with anisocytosis and polychromasia, nucleated RBCs as 8/100 WBC, and 5% atypical mononuclear cells. Bone marrow revealed 26% blasts with high nucleocytoplasmic ratio. Erythroid precursors comprise 52% of all nucleated cells without the presence of megakaryocytes. Immunophenotyping revealed two cell populations: one was with CD45, moderate expression of cytoplasmic myeloperoxidase and CD117, CD13, CD33; however, negative for B-/T-lymphoid markers. The other population presented low-to-intermediate side scatter and negative for CD45, dim expression of CD235a (64%), indicating lysis-resistant abnormal erythroid progenitors. The pattern of myeloid antigen positivity and erythroid progenitors was consistent with the diagnosis of AML, more specifically erythroleukemia (FAB: AML-M6). Similar CD13/33 positivity was reported by Pediatric Oncology Group (POG) 8498.
Conventional cytogenetic analysis was carried out on thirty metaphases obtained from unstimulated bone marrow culture. Karyotyping revealed highly complex rearrangements involving 17 chromosomes, namely, 1/5/6/7/8/9/10/12/13/14/15/17/18/19/21/22/X in single or both copies, with a total of 39 chromosomes. Structural rearrangements including der(1p)/del(8q22)?t(8;21)/del(9q)/der(12)t(12p;?)/t(13;14)/t(14;15)/i(17q)/?t(19p;?) and multiple of complex rearrangements resulting in several marker chromosomes were present in all cells [Figure 1]. Trisomy 21 could not be distinguished due, most likely, to its rearrangement in some of the marker chromosomes. The International System for Human Cytogenetic Nomenclature classification may not be very accurate due to complexity of rearrangements and inadequate morphology.
|Figure 1: Description on chromosomal rearrangements and clonal abnormalities in a Down syndrome patient developed acute myeloid leukemia. (a) Der(1p),-5,-6,der(8)?t(8;21),del(9q),-10,der(12p),-13,-14?t(13;14),-15?t(14;15),-17,i(17q),-18,-18,-19,der(21),-22,-X,+5mar. (b) Der(1p),-5,-6,-7,-8,der(8)?t(8;21),del(9q),-10,der(12p),-13,-14?t(13;14),-15?t(14;15),-17,i(17q),-18,-18,-19,-22,+6mar. (c) Der(1p),-4,-5,-6,-7,-8,der(8)?t(8;21),del(9q),-10,der(12p),-13,-14?t(13;14),-15?t(14;15),-17,i(17q),-18,-18,-19,der(21),-22,-X,+7mar|
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| > Discussion|| |
Despite the fact that high predisposition of DS children to leukemia have been recognized over 60 years, relatively low frequency of the cases has been documented for clonal genetic alterations and leukemia-related mortality. The systematic evaluation of the pathogenesis and outcome of chemotherapeutic drugs has been limited due to high morbidity and mortality among these genetically incompetent children. Recent development on understanding clinical impact of overexpression of HSA21 and involvement of ETS family genes at 21q22 in DS leukemogenesis is under progress.,,
Genomic instability and heterogeneity of the neoplastic cell population were demonstrated with common and/or overlapping chromosomal aberrations, which result from clonal evolution in AL with DS (DS-AL). Surprisingly, besides +21, individual case reports could not capture the specific cytogenetic alterations in DS-leukemia because of limited cases published. Acquired abnormalities, including hyperdiploidy, trisomy (8/21/19/22), and structural rearrangements, were observed in DS-AML and DS-cell lines.,,, Del (5)(q31q33) and t(16;20)(q13;q12) were reported in a DS-AML female. Trisomies of 8/11/13/16/21 and structural rearrangements including t(8q;16q)/der(12)/t(3;6) reported in DS-AML were not significantly different from non-DS-leukemia children. Therefore, there is as yet no clear chromosome clue as to the precise basis of the etiologic clonal development in DS-AL and associated survival.
The treatment of DS-AL and outcome remained controversial in the past based on the fact of DS sensitivity to chemotherapeutic drugs, toxicity, and increased rate of infections. However, POG 8498 protocol comprising daunorubicin, cytarabine (Ara-C), and 6-thioguanine for remission induction and featured high-dose Ara-C with or without L-asparaginase has presented a superior EFS compared to non-DS counterpart. High dose of Ara-C has eliminated the acquired t(16;20), del(5q). Superior EFS was thought to be favored by a low initial WBC (<100,000/L) and age ≤2 years. Our case with low WBC and 2 years of age may not achieve a favorable prognosis due to complexity of rearrangements.
The frequently noted superior response in AML with t(8;21) having a breakpoint at 21q22 could potentially result in increased expression of purine synthetic enzymes and cystathionine synthase, which is assigned to 21q22.3. The observation of the linkage of reduced function-associated GATA1 mutations with DS-AMkL/TMD and folate pathway to cytarabine sensitivity as well as the pivotal role of SOD1 mutation increasing reactive oxygen species in determining cellular sensitivity to chemotherapeutic agents and induction of toxicity have provided a great impetus to understand the mechanistic basis of pathogenesis and drug sensitivity of DS-AML.,,
Nevertheless, the treatment outcome and EFS depend on the nature of acquired clonal chromosomal alterations. Poor prognosis of erythroid leukemia with 4–6 months of median survival has been described with complex cytogenetic result. Our case with a multitude of complex numerical/structural abnormalities could not be followed up due to relocation of the family, and thus, no definite comment could be made on her survival.
It is clear that DS is a unique paradigm for understanding the increased risk for leukemogenesis and drug sensitivity for other constitutional chromosomal disorders. However, several questions that are specific to complex cytogenetics-related survival of DS-AL remain to be elucidated. Our case with a wide spectrum of complex rearrangements might be the first of its kind and indicates the importance of such data along with supportive literature for better understanding of diagnosis and prognostic management of DS-AL.
We wish to acknowledge the patient's parents for their consent for this publication.
Financial support and sponsorship
Mahatma Gandhi Mission New Bombay Hospital has extended institution grant for supporting this research and publication.
Conflicts of interest
There are no conflicts of interest.
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