3q26 chromosomal anomalies in acute myeloid leukemia: First descriptions from IndiaA Gupta, L Kumar
Departments of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_727_16
Source of Support: None, Conflict of Interest: None
Keywords: 3q26, acute myeloid leukemia, cytogenetics, inversion, translocation
Chromosomal anomalies involving the 3q26 region are rare in acute myeloid leukemia (AML). Various studies have estimated their incidence to be ranging from 3% to 5%. Recent studies suggest that their incidence may be close to 7%–10%., These anomalies are associated with normal or elevated platelet counts and very poor or no response to chemotherapy resulting in a dismal prognosis.,,,,,,,, There are no descriptions of this anomaly from the Indian subcontinent.
Between January 2001 and January 2008, 174 cases of AML were treated at our hospital. Cytogenetic analysis of 115 cases was able to be performed and revealed three cases (2.7%) to be harboring the chromosome 3q26 anomaly. Institute Ethics Committee clearance was obtained before undertaking this study.
A 42-year-old male patient presented to us with a 1-year history of fatigue and progressive weakness [Table 1] and [Figure 1].
A 15-year-old boy presented to us with 3 months history of intermittent fever, fatigue, weakness, pain in calves, and gum bleeding [Table 1] and [Figure 2]a.
A 45-year-old male patient presented with 2 months history of progressive weakness, intermittent fever, and reduced appetite [Table 1] and [Figure 2]b.
3q21;q26 cytogenetic anomalies are characterized by morphologic abnormalities of thrombopoiesis in the bone marrow, patients present with higher platelet count at diagnosis as compared with non-3q rearranged ones and some cases can present with normal or elevated platelet counts as well. They are also associated with chromosomal 7 abnormalities (usually monosomy 7) and central diabetes insipidus. The most common anomalies are inv(3)(q21q26) and t(3;3)(q21q26).,,,
The ins(3)(q26;q21q26) anomaly is rare. Associated chromosomal anomalies include - 7/del(7q) (most common), -5/del(5q), del(6q) and del(20q).,,,,,, Aberrant expression of EVI1 gene has been reported almost exclusively in cases presenting with translocations involving band 3q26. EVI1 gene expression by retroviral vectors has been found to block the granulocyte colony-stimulating factor-induced differentiation of murine myeloid cells. ribophorin 1 (RPN1) at location 3q21 gets juxtaposed to 3q26 resulting in its activation.,,,
The translocation t(2p; 3q) anomaly as seen in our second case is of two types. In one type the breakpoint on chromosome 2 is localized to bands 2p21-23, whereas the breakpoint for the other is localized to 2p15-21. This also results in activation of the EVI1 gene. It can exist as a sole anomaly/be associated with -7, del(5q), del(7q), t(9;22)(q34;q11) or with complex karyotypes. Features are typical of 3q26/EVI1 rearrangements as described above. Aberrations involving 3q26 have been described in all AML subtypes (except AML-M3), chronic myeloid leukemia blast crisis, and myelodysplastic syndrome.,,
In our study also the anomaly was not restricted to any particular subtype (our cases had AML-M2, AML-M4, and AML-M1, respectively). We also did not find organomegaly, lymphadenopathy, or central diabetes insipidus at presentation.
There was also no evidence of central diabetes insipidus - a condition that has been found to be associated with this anomaly. Some series have noted a striking predilection for males while some have not. Preferential involvement of women in t(3;3) has been described. None of our patients harbored the t(3;3) anomaly. Leukocytosis was not pronounced. The third case had leukopenia.
The common features seen in the first two cases (all the metaphases involved) were the presence of only mild thrombocytopenia (relatively high platelet counts when assessed against the background of AML with high blast percentages), monosomy 7, myeloperoxidase positive blasts, mild eosinophilia, and poor or no response to therapy. They refused the option of allogenic transplantation. However, reports indicate that transplantation is also associated with poor results.
In the third case, the chromosome 3 anomaly was present in only one metaphase. The patient responded to induction therapy. He relapsed after having been in complete remission for 15 months. These cytogenetic features are unique and not described in the literature. The clinical behavior in the third case was typical of AML-M1, and he showed response to chemotherapy. The 3q26 anomaly detected in our third case was present in only one metaphase but appears clinically significant given the nature of the anomaly.
The precise mechanisms underlying the role of this anomaly in leukemogenesis needs to be elucidated and better treatments devised since these patients respond poorly to therapy.
Recent reports show that a substantial part of the EVI-1-positive AML cases respond to all-trans retinoic acid (ATRA) by induction of differentiation and decreased the clonogenic capacity of myeloid blasts. Most importantly, treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Combining ATRA with the currently used conventional chemotherapy might thus be a promising treatment strategy in a disease otherwise associated with dismal prognosis.
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[Figure 1], [Figure 2]