Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: an overview.
Abstract: Acute myelogenous leukemia (AML) with chromosomal translocation (6;9)(p23;q34) is a rare disease with poor prognosis and distinct clinical and morphologic features. t(6;9) results in a chimeric fusion gene between DEK (6p23) and CAN/NUP214 (9q34). FLT3-ITD mutation is one of the most frequent mutations in AML and correlates with poor clinical outcome. Prevalence of FLT3-ITD is as high as 70% among patients with t(6;9) AML, and patients with t(6;9) AML and FLT3-ITD mutations usually have higher white blood cell counts, higher bone marrow blasts, and significantly lower rates of complete remission. t(6;9) is most commonly associated with AML-FAB-M2 and is considered by some researchers to be a separate disease entity because of its distinct clinical and morphologic features and poor prognostic implication. Distinct morphologic features of this entity include marrow basophilia and myelodysplasia, and immunophenotypically, the blast cells are positive for CD9, CD13, CD33, and HLA-DR; are usually positive for CD45 and CD38; and may be positive for CD15, CD34, and terminal deoxynucleotidyl transferase.
Article Type: Disease/Disorder overview
Subject: Cancer (Genetic aspects)
Cancer (Research)
Bone marrow (Diseases)
Bone marrow (Development and progression)
Authors: Chi, Yiqing
Lindgren, Valerie
Quigley, Sean
Gaitonde, Sujata
Pub Date: 11/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Nov, 2008 Source Volume: 132 Source Issue: 11
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246876
Full Text: Acute myelogenous leukemia (AML) with translocation involving breaks at band 23 of the short arm of chromosome 6 and band 34 of the long arm of chromosome 9, t(6;9)(p23;q34), is a rare disease and constitutes 0.5% to 4% of all AML cases. (1) This translocation results in the formation of a chimeric fusion gene (DEK-NUP214)on the derivative chromosome 6, der(6), and was first identified in AML by Rowley and Potter in 1976. (2) Most patients with this disease are diagnosed with AML according to the French-American-British classification (AML-FAB) of M2 or M4, and many show evidence of underlying or preceding myelodysplasia. Prognosis is usually poor, and complete remission is achieved with conventional chemotherapy in only 50% of the cases. Median survival is dismal (<1 year from diagnosis). Bone marrow transplantation improves survival and may be the only modality to achieve cure.

CLINICAL FEATURES

Acute myelogenous leukemia with t(6;9)(p23;q34) usually affects younger individuals (median age, 23 years; range, 2-66 years), with both sexes equally affected. Most patients present with de novo AML. The symptoms are due to the cytopenias often seen in leukemia (fatigue because of anemia, bleeding tendencies because of thrombocytopenia, and increased incidence of infections).

LABORATORY FINDINGS

The complete blood cell count in t(6;9) AML usually reveals findings of bone marrow failure. There is anemia, thrombocytopenia, and circulating blasts (Figure 1). Children tend to present with lower hemoglobin values and higher white blood cell counts than adults. In fact, adults usually present with white blood cell counts lower than those seen in AML in general. (3)

PATHOLOGY

The bone marrow (Figure 2) in t(6;9) AML is usually hypercellular for the patient's age, with increased blasts (>20%), which may show Auer rods or granules. Interestingly, bone marrow basophilia and unilineage or multilineage dysplasia may be seen in residual hematopoietic cells (4) (Figures 3 and 4). Alsabeh et al (5) reported an increased incidence of ringed sideroblasts as a sign of myelodysplasia in these patients. To our knowledge, the only large retrospective study (6) to date on this entity (collaboration of 5 cooperative groups: Southwest Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Children's Oncology Group, and Children's Cancer Group) reported a prevalence of 44% for marrow basophilia and 67% for myelodysplasia evidence.

Immunophenotypically, t(6;9) AML blast cells are positive for CD9, CD13, CD33, and HLA-DR;usually positive for CD45 and CD38;and may be positive for CD15, CD34, and terminal deoxynucleotidyl transferase. (7) Alsabeh et al (5) reported an initial immunophenotype of [CD34.sup.-] blasts, which usually relapsed as [CD34.sup.+].

ANCILLARY STUDIES

Cytogenetic analysis and molecular detection of the DEK-NUP214 fusion gene by polymerase chain reaction (PCR) are very important ancillary studies in making the diagnosis of AML with t(6;9). This is demonstrated by a morphology (usually AML-FAB-M2 or occasionally M4) and immunophenotype that are not diagnostic of this entity. Presence of basophilia and myelodysplasia in an AML-FAB-M2 suggest this diagnosis, but it must be confirmed by cytogenetic and molecular analysis.

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In most cases, t(6;9) is the only cytogenetic aberration (Figure 5). It results in a chimeric fusion gene between DEK (6p23) and NUP214 (9q34;formerly known as CAN). This fusion gene encodes a messenger RNA involved in leukemogenesis. The NUP214 is a putative oncogene with multiple fusion gene-peptide sequence motifs, and it encodes a nuclear pore complex protein associated with nucleocytoplasmic transport. It may be activated by fusion of its 3' end to other genes, like DEK. (8)

The breakpoints in DEK and NUP214 are tightly clustered within introns, which allow detection of DEKNUP214 fusion transcripts by molecular techniques like reverse transcriptase-PCR and Southern blot analysis. Garcon et al (8) studied real-time quantitative PCR levels of DEK-NUP214 transcripts in 12 patients. They found that molecular analysis of DEK-NUP214 is useful in follow-up of the disease and that reverse transcriptase-PCR that is negative for DEK-NUP214 correlates strongly with patient survival.

Although it may be true that the DEK-NUP214 fusion gene is responsible for the poor prognosis, studies have demonstrated a high prevalence (70%) of the /ms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation among patients with t(6;9) AML. (6,9) That prevalence is definitely higher than that seen in all other types of AML. The FLT3 gene is involved in the proliferation and differentiation of hematopoietic stem cells. The mutation is one of the most frequent mutations in AML and correlates with poor clinical outcome. (10) Thiede et al (9) showed that patients with t(6;9) and FLT3-ITD mutations have higher white blood cell counts, higher percentages of bone marrow blasts, and significantly lower rates of complete remission.

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CURRENT THERAPY

The type of chemotherapy and autologous stem cell transplant does not change the poor outcome for patients with AML and t(6;9) and FLT3-ITD mutations. Allogeneic stem cell transplant may, however, be associated with better overall survival, similar to all AML with poor cytogenetic risk factors. t(6;9) AML may warrant a prospective multicenter investigation of aggressive and novel therapeutic strategies. A clinical trial of anti-CD33-based therapies plus an FLT3 inhibitor for patients without suitable donors may be helpful.

PROGNOSIS

Patients with AML and t(6;9) have very poor prognoses, short disease-free survival times, and dismal overall survival rates.6 Age is not a prognostic factor. High peripheral white blood cell counts correlate with a poor outcome in overall survival, and high marrow blast counts are predictive of short disease-free survival times. Patients who achieve prolonged molecular remission fare better.

CONCLUSION

Patients with t(6;9) AML have a very poor prognosis. The currently available chemotherapy does not seem to improve overall survival. However, accurate diagnosis is crucial because these patients may benefit from early allogeneic stem cell transplant. Improved novel therapies such as anti-CD33-based therapies and FLT3 inhibitors need to be evaluated. Molecular follow-up of minimal residual disease is helpful in stratifying risk and in managing a patient's disease. The World Health Organization classification of hematopoietic tumors stresses the importance of prognostic implications of cytogenetic abnormalities in hematopoietic malignancies. Acute myelogenous leukemia with t(6;9)(p23;q34), although rare, warrants being added as a separate category under AML with recurrent cytogenetic abnormalities because of its distinct morphologic, cytogenetic, and clinical features.

Accepted for publication May 8, 2008.

References

(1.) Schwartz S, Jiji R, Kerman S, Meekins J, Cohen MM. Translocation (6;9)(p23; q34) in acute nonlymphocytic leukemia. Cancer Genet Cytogenet. 1983;10:133-138.

(2.) Rowley JD, Potter D. Chromosomal banding patterns in acute nonlymphocytic leukemia. Blood. 1976;47:705-721.

(3.) Pearson MG, Vardiman JW, Le Beau MM, et al. Increased numbers of marrow basophils may be associated with t(6;9) in ANLL. Am J Hematol. 1985;18: 393-403.

(4.) Rowley JD. Recurring chromosome abnormalities in leukemia and lymphoma. Semin Hematol. 1990;27:122-136.

(5.) Alsabeh R, Brynes RK, Slovak ML, et al. Acute myeloid leukemia with t(6; 9)(p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol. 1997;107:430-437.

(6.) Slovak ML, Gundacker H, Bloomfield CD, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies. Leukemia. 2006;20:1295-1297.

(7.) Oyarzo MP, Lin P, Glassman A. et al. Acute myelogenous leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high frequency of FLT3 gene mutations. Am J Clin Pathol. 2004;122:348-358.

(8.) Garcon L, Libura M, Delabesse E, et al. DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification. Leukemia. 2005;19: 1338-1344.

(9.) Thiede C, Steudel C, Mohr B, etal. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326-4335.

(10.) Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19:1345-1349.

Yiqing Chi, MD; Valerie Lindgren, PhD; Sean Quigley, MD; Sujata Gaitonde, MD

From the Departments of Pathology (Drs Chi, Lindgren, and Gaitonde) and Medicine (Dr Quigley), University of Illinois, Chicago.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Sujata Gaitonde, MD, Department of Pathology (MC 847), UIC College of Medicine, 1819 W Polk St, Chicago, IL 60612 (e-mail: sgaitond@uic.edu).
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