3q26 chromosomal anomalies in acute myeloid leukemia: First descriptions from India.

Cytogenetic anomalies involving the 3q26 chromosomal region are rare in acute myeloid leukemia (AML). There is no such description of these anomalies from the Indian sub-continent. A total of 174 AML patients were admitted to our hospital for therapy between January 2001 and January 2008. Cytogenetic studies could be done in 115 patients; which revealed three cases with 3q26 anomalies. All were males. In the first two cases, the anomaly was detected in all the metaphases. The common features seen 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 therapeutic response. In the third case, the chromosome 3 anomaly was present in only one metaphase. Such an anomaly has not been reported. Only the third patient responded to induction therapy but subsequently relapsed after being in complete remission for 15 months. 3q26 anomalies are associated with monosomy 7, relatively higher platelet counts at diagnosis as compared with other non-3q rearranged AML's and poor prognosis. The precise mechanisms underlying leukemogenesis need to be elucidated and better treatments devised since these patients respond poorly to therapy.

Introduction

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%.[1] Recent studies suggest that their incidence may be close to 7%–10%.[23] These anomalies are associated with normal or elevated platelet counts and very poor or no response to chemotherapy resulting in a dismal prognosis.[456789101112] 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.

Case Reports

Case 1

A 42-year-old male patient presented to us with a 1-year history of fatigue and progressive weakness [Table 1 and Figure 1].

Table 1

Disease characteristics and response to therapy

Parameters	Case 1	Case 2	Case 3
Age/sex	42/male	15/male	45/male
History, exposure to chemotherapy/carcinogens	1 year, none	3 months, none	2 months, none
Organomegaly, other findings, diabetes insipidus	None	None	None
	Mild pallor	Pallor	Pallor
	No	No	No
Hemoglobin (g%)	7.6	4.9	6.1
Total leucocyte count (×109/L)	14.2	9	2.4
Platelet count (×109/L)	99.2	100	20
Peripheral smear	41% blasts	54% blasts	71% blasts
Bone marrow findings	54% blasts, MPO positive, dysplastic megakaryocytes	70% blasts, MPO positive, dysplastic megakaryocytes	90% blasts: Occasionally MPO positive
AML subtype	M2	M4	M1
Flow cytometry	HLADR+, CD34+, CD13+, CD33+, CD14−, CD15−, CD117+, MPO+, CD41−, CD61−	HLADR+, CD34−, CD13+, CD33+, CD14+, CD15+, CD117−, MPO+, CD41−, CD61−	HLADR+, CD34+, CD13+, CD33+, CD14−, CD15−, CD117+, MPO+, CD41−, CD61−
Cytogenetics	Para-centric inversion - long arm of chromosome 3, monosomy 7: In all 20 metaphases studied 45 inv (3)(q21q26), -7	Reciprocal translocation - short arm of chromosome 2 and long arm of chromosome 3, monosomy 7: In all 20 metaphases studied 45 XY (t2;3)(p22q26), -7	1 metaphase-trisomy 3, inversion of part of long arm of chromosome 3.19 metaphases XY, normal 46 XY (19)/47 XY inv (3)(q21,26), +3 (1)
Therapy	Induction 7+3, no response, day 21 marrow 41% blasts Reinduction: HiDAC, day 21 blasts 12%	Induction 7+3, no remission, day 21 marrow 49% blasts Reinduction: HiDAC, day 21 blasts 15%	Induction 7+3, CR consolidation: 3 courses HiDAC
Response	No response	No response	Relapse after 15 months
Overall survival	Overall survival: 3 months	Overall survival: 4.2 months	Overall survival: 19 months

7+3: Daunomycin 60 mg/m2 for 3 days and cytarabine 100 mg/m2 continuous infusion for 7 days, MPO: Myeloperoxidase, HiDAC: High dose cytarabine - 18 g/m2, AML: Acute myeloid leukemia, CR: Complete remission, HLADR: Human Leukocyte Antigen - antigen D Related

Figure 1

Case 1: Para-centric inversion – long arm of chromosome 3, monosomy 7: 45, inv(3)(q21q26), -7

Case 2

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 2a].

Figure 2

(a) Case 2: Reciprocal translocation-short arm of chr 2 and long arm of chromosome 3, monosomy 7: 45, XY t(2,3)(p22, q26), -7. (b) Case 3: Trisomy 3, inversion of part of long arm of chromosome 3: 47 XY inv(3)(q21,26), +3

Case 3

A 45-year-old male patient presented with 2 months history of progressive weakness, intermittent fever, and reduced appetite [Table 1 and Figure 2b].

Discussion

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).[1234]

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).[567891011] 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.[9101112]

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.[7] Aberrations involving 3q26 have been described in all AML subtypes (except AML-M3), chronic myeloid leukemia blast crisis, and myelodysplastic syndrome.[145]

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.[10] Some series have noted a striking predilection for males while some have not.[1] Preferential involvement of women in t(3;3) has been described.[8] 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.[12]

Declaration of patient consent

The authors certify that appropriate patient consents were obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.