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Keywords: Cancer cytogenetics; Clinical cytogenetics; Oncogenesis; Molecular cytogenetics; Genomic structure

Authors:
J. Liu 1; S. Gargan 1; N. Nwaoduah 1; Z. Wang 1; J. Gong 1; G. Uppal 1; D. Foster 1; R. Bajaj 2; S. Peiper 1

Affiliations:
1) Pathology, Anatomy and Cell Biology, Thomas Jefferson Univ, Philadelphia, Pennsylvania.; 2) Clinical and Molecular Cytogenetics, Section of Pathology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania.


The Philadelphia chromosome (Ph) resulting from a reciprocal translocation t(9;22)(q34;q11) is a characteristic finding in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (ALL) as well as rarely in acute myeloid leukemia (AML). The derivative chromosome contains the BCR-ABL1 fusion gene that encodes for a protein with constitutive protein kinase activity. Amplification of BCR-ABL1 and mutations in the ABL1 kinase domain have been described in Ph+ leukemia cases that were resistant to tyrosine kinase inhibitor (TKI). Here we report three new Ph+ acute leukemia cases with amplification of the BCR-ABL1 fusion. Case 1 is a 35 year-old male with Ph+ ALL who underwent two allogeneic stem cell transplantations and treatment with multiple TKIs, and upon his second relapse demonstrated complex karyotype (50-51,XY,add(4)(q35),+8,t(9;22)(q34;q11),del(10)(q24),del(12)(q24.1),+17,+18,+20,der(22)t(9;22)(q34;q11)x1-2,+1-4mar[cp20]), amplification of Ph+ by fluorescence in situ hybridization (FISH), and multiple ABL1 kinase mutations. This patient was TKI-refractory and succumbed to his disease 7 years after diagnosis. Case 2 is a 77 year-old female with newly diagnosed AML had a complex karyotype (44~46,XX,t(1;3)(p36;p21),-4,-5,add(10)(p11.2),der(22)t(9;22)(q34;q11.2),+mar[20]), BCR/ABL1 translocation with both Ph and MLL amplification and TP53 deletion. This is the first documented case of AML with t(1;3) in conjunction with t(9;22) and Ph amplification. Case 3 is 60 years old male with newly diagnosed AML. Complex karyotype 51-69,XY,+Y,+1,+2,+3,+6,i(6)(p10),+8,t(9;22)(q34;q11.2),+10,+11,+12,+13,del(13)(q12q14),+14,+15,+16,+18,+19,+20
,+der(22)t(9;22)[cp4]/46,XY[10] was seen by cytogenetics and BCR/ABL1 translocation with Ph amplification seen by FISH. The patient was given induction chemotherapy but deceased two month late due to severe sepsis and cardiogenic shock. These three cases illustrate the genetic heterogeneity of Ph-positive leukemias. Numeric and/or structural cytogenetic aberrations, as well as ABL1 kinase mutations, may be present at initial diagnosis or acquired with disease progression, and they are associated with an aggressive disease course and resistance to TKI therapy. Understanding the underlying molecular pathogenesis and appropriate of such cases would help to provide more effective clinical management.