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A complex karyotype with t(11;12)(q23;p13) translocation with coexistent clones of deletion 5q and cryptic deletion 7q in acute myeloid leukemia

 Department of Medical Genetics, Metropolis Healthcare Ltd., Mumbai, Maharashtra, India

Date of Submission20-Jul-2018
Date of Decision07-Nov-2018
Date of Acceptance21-Nov-2018
Date of Web Publication08-Jul-2020

Correspondence Address:
Anurita Pais,
Department of Medical Genetics, Metropolis Healthcare Ltd., Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_473_18

PMID: 32675439


We report a rare case of acute myeloid leukemia (AML) with a cytogenetically complex karyotype with coexistence of KMT2A/MLL Mixed Lineage Leukemia (11q23) rearrangement with 5q deletion and 7q deletion as unrelated clones along with evolution of a subclone with translocation between chromosomes 6 and 17. A novel MLL fusion partner region 12p13 was identified in a 52 year old woman who presented with pyrexia of unknown origin. Unraveling the complexity of genomic alterations occurring in AML patients will lead to better understanding of leukemic transformation and identification of subsets of patients that may respond differently to therapy.

Keywords: Acute myeloid leukemia, FISH, karyotyping, MLL, rearrangements

How to cite this URL:
Pais A, Pande S, Pradhan G, Patil S. A complex karyotype with t(11;12)(q23;p13) translocation with coexistent clones of deletion 5q and cryptic deletion 7q in acute myeloid leukemia. Indian J Cancer [Epub ahead of print] [cited 2020 Aug 9]. Available from:

  Introduction Top

Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with variability in clinical course and response to therapy based on the genetic and molecular pathology that stand as the most important prognostic factors.[1],[2] Among the recurrent cytogenetic markers in AML, a complex aberrant karyotype is a distinct biological entity associated with poor prognosis and also characterized by genomic imbalances and a specific gene expression profile.[1] Refinement of prognosis in AML is based on comprehensive analysis of cytogenetic alterations as well as gene mutations, which are useful for risk-adapted therapeutic management of AML patients.[3],[4]

In a population-based study, it was estimated that the incidence of karyotypically complex AML with three or more aberrations in the German population was 0.05 per 100,000 people aged 21–30 years, but it was almost 25 times higher - 1.15 per 100,000 people in the 61- to 70-year age group. 2017 European LeukemiaNet (ELN) risk stratification categorizes complex karyotype and KMT2A rearrangement into an adverse risk category.[5]

Cytogenetically unrelated clones are uncommon findings in hematological disorders, occurring with frequencies of 4.3%–6.5% in myelodysplastic syndrome, 1.1%–3.7% in AML, 0%–0.6% in acute lymphoblastic leukemia, and about 7.3% in chronic lymphocytic leukemia.[6],[7]

We report a rare case of AML with a cytogenetically complex karyotype with coexistence of MLL (KMT2A-MLL Mixed Lineage Leukemia, 11q23 locus) rearrangement with 5q deletion and 7q deletion. Analysis revealed a subclone evolution of translocation between chromosomes 6 and 17 that was assessed by clonal percentage of each clone by fluorescence in situ hybridization (FISH) analysis. We also report identification of a novel MLL fusion partner region 12p13 with variant rearrangement that adds to the list of the 135 different MLL partner genes that have been described till date in literature.[8]

  Case History Top

A 52 year old woman was referred to Metropolis healthcare laboratory with a history of pyrexia of unknown origin. Her peripheral blood showed 90% blasts with platelet count of 30,000. Her hemoglobin was 6 g/dL.

Bone marrow smear examination showed myeloid series suppressed with 79% blasts, erythroid series suppressed with occasional normoblast, and absence of megakaryocytes.

Further, immunophenotype analysis revealed that bone marrow blasts showed dim to moderate positivity for HLA-DR (31.6%), CD34 (51.6%), CD4 (63.4%), CD19 (30%), CD13 (72.4%), CD33 (75.2%), CD117 (48.6%), cMPO (96.1%), CD14 (32%), and CD64 (80%) and positive with moderate to bright for CD11c (93.1%) and CD15 (38.8%), classifying the patient as AML with monocytic differentiation (AML-M5b).

Conventional cytogenetic study on bone marrow cells showed a complex subclonal karyotype 46, XX, del(5)(q15q33), t(11;12)(q23;p13)[8]/46, sl, t(6;17)(p21;q21)[12] with involvement of three chromosomal abnormalities along with MLL gene rearrangement positive status due to translocation between chromosomes 11 and 12;t(11;12) to a new partner region on chromosome 12 at region p13. The clone with interstitial deletion 5q15q33 and translocation t(11;12)(q23;p13) was the basic clone and hence represented the stem line (sl). The other subclone as a result of clonal evolution was translocation t(6;17)(p21;q21). FISH studies were performed to characterize the complex chromosomal abnormalities identified. To confirm the involvement of MLL gene rearrangement translocation t(11;12), FISH study showed MLL gene rearrangement positive status with a variant pattern of deletion of the 3′ part of the MLL gene and duplication of the 5′ region, which was observed as 1 fusion (yellow) and 2 red (spectrum orange) in 98% of cells. The duplicated 5′ region was observed on chromosome 12 at region p13 as assessed by Karyotyping and FISH [Figure 1], [Figure 2], [Figure 3]. FISH also confirmed the positive status for deletion 5q at region 5q15 to q33. Although karyotype analysis showed normal chromosome 7, FISH analysis revealed a submicroscopic interstitial deletion at 7q31. FISH studies for AML markers, such as PML/RARA: t(15;17), RARA variants, AML1/ETO: t(8;21), and inversion 16, showed negative status. FISH studies also confirmed negative status for 17p (p53) deletion [Figure 4].
Figure 1: 46,XX,del(5)(q15q33),t(11;12)(q23;p13)[8]/46,sl,t(6;17)(p21;q21)[12]. Karyotype analysis revealed presence of a complex karyotype with three chromosomal abnormalities also involving MLL gene rearrangement. The clone with interstitial deletion 5q15q33 and translocation t(11;12)(q23;p13) is the basic clone and hence represents the stemline (sl). The other subclone as result of clonal evolution is translocation t(6;17)(p21;q21)

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Figure 2: Fluorescence in situ hybridization with MLL probe show yellow signal of normal MLL allele on homolog 11, and two orange signals indicating duplication of the 5' region and deletion of the 3' part of the MLL gene (loss of green signal)

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Figure 3: Ideogram of the variant rearrangement of MLL gene on chromosomes 11 and 12

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Figure 4: FISH using chromosome region 7q31 (orange labeled) and CEP 7 (green labeled) probe on interphase cell showing two green signals and one orange signal indicating deletion of 7q31

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  Discussion Top

AML patients with a complex karyotype defined as three or more aberrations consistently constitute 10%–12% of all patients analyzed and increases with age;[9-11] the most common genomic imbalances (losses and gains) affecting specific chromosome arms in AML patients with complex karyotypes are the 5q and 7q deletion.[12]

To our knowledge, this is the first reported case of MLL gene translocation to chromosome 12p13 region with a variant pattern with coexisting 5q and 7q deletions. Our study revealed a novel MLL partner region adding up to the list of 135 known MLL partner chromosome regions. Double-mutational mechanism in MLL was revealed by the aberrant variant FISH pattern. Identification of a novel MLL fusion partner region 12p13 leading to the formation of an unknown novel fusion protein suggests the need for further search for the gene involved and the molecular mechanisms of leukemic transformation mediated by MLL fusion protein. Understanding of the molecular pathway led by MLL translocations and the contribution of the different fusion partners can help guide targeted treatments. In our case, presence of a primary clone of MLL, 5q and 7q deletion along with subclone formation of t(6;7) has led to increase in complexity of the karyotype with a proliferative advantage and that such patients with AML with cytogenetic adverse risk and clonal heterogeneity would classify into an adverse-risk category significantly influencing survival and may benefit from autologous stem cell transplant.[13]

Unraveling the complexity of genomic alterations occurring in AML patients with multiple chromosome aberrations will lead to better understanding of biological basis of leukemic transformation and will also result in identification of cytogenetic and molecular subsets of patients that may respond differently to therapy. Further characterization of such genetic alterations will likely allow development of targeted therapeutic approaches that will improve the currently very poor prognosis of AML patients with a complex karyotype.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


The authors are grateful to the management of Metropolis Healthcare Ltd., Mumbai, for providing the necessary infrastructure facilities. We are also thankful to Ms Ankita Chaurasia for formatting the manuscript.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev 2004;18:115-36.  Back to cited text no. 1
Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36.  Back to cited text no. 2
Haferlach T, Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2008;400-11. doi: 10.1182/asheducation-2008.1.400.  Back to cited text no. 3
Mrózek K, Acute myeloid leukemia with a complex karyotype. Semin Oncol 2008;35:365-77.  Back to cited text no. 4
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424-47.  Back to cited text no. 5
Han JY, Theil KS, Hoeltge G. Frequencies and characterization of cytogenetically unrelated clones in various hematologic malignancies: Seven years of experiences in a single institution. Cancer Genet Cytogenet 2006;164:128-32.  Back to cited text no. 6
Han JY, Kim KH, Kwon HC, Kim JS, Kim HJ, Lee YH, et al. Unrelated clonal chromosome abnormalities in myelodysplastic syndromes and acute myeloid leukemias. Cancer Genet Cytogenet 2002;132:156-8.  Back to cited text no. 7
Meyer C, Burmeister T. The MLL recombinome of acute leukemias in 2017 Leukemia 2018;32:273-284.  Back to cited text no. 8
Stölzel F, Mohr B, Kramer M, Oelschlägel U, Bochtler T, Berdel WE, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J 2016;6:1-7.  Back to cited text no. 9
Mrozek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol 2012;30:4515-23.  Back to cited text no. 10
Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: Evaluation of the proposed reporting system. J Clin Oncol 2011;29:2758-65.  Back to cited text no. 11
Tennant TR, Huo D, Davis EM, Larson RA, Le Beau MM. Genomic rearrangements associated with -5/del(5q) and -7/del(7q) in myeloid leukemias. Blood 2007;110:1813.  Back to cited text no. 12
Bochtler T, Stölzel F. Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. J Clin Oncol 2013;31:3898-907.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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