Final Diagnosis -- Acute Myeloid Leukemia with INV(3)(q21q26)



This case represents a relatively newly recognized subtype of AML, with specific prognostic factors and somewhat characteristic morphologic and other associated cytogenetic findings. In the 2008 WHO Classification of Hematopoietic and Lymphoid tumors, this case fulfills criteria for a diagnosis of "AML with inv(3)(q21q26)." Also included in this category are cases with a translocation from one copy of chromosome 3q to the other chromosomal partner--t(3;3)(q21;q26.2). The critical affected genes in these translocations involved disruptions in the RPN and EVI1 genetic loci. AML with inv(3)(q21q26) or t(3;3)(q21;q26.2); RPN1-EVI1 represents 1-2% of all AML cases, and is most commonly seen in adults, without a gender predilection.

This form of AML may be associated with normal or increased platelet counts. Atypical, dysplastic megakaryocytes - especially small, monolobate forms - can often be present, as well as associated multilineage dysplasia. It often shows overlapping features with acute megakaryoblastic leukemia (AML-M7), but does not generally show all the features characteristic of that morphologic subtype.

This form of AML does not have a specific set of immunophenotypic features. Blast cells are typically positive for CD13, CD33, HLA-DR, CD34 and CD38. Aberrant expression of CD7, CD41 and CD61 may occur in some cases; the latter two are usually in a subset of the blast population.

Common secondary cytogenetic abnormalities associated with AML with inv(3)(q21q26) include monosomy 7 (seen in 50% of patients), del 5q and a complex karyotype - all of which were identified in this particular case.

The critical oncogenes that appear to be involved in the pathogenesis of this AML subtype are EVI1 and RPN, located on 3q26.2 and 3q21, respectively. It is postulated that abnormalities in chromosome 3 cause RPN1 to enhance EVI1 expression, which causes greater cell proliferation with an impairment in differentiation. This is in contrast to leukemias harboring the t(3;21)(q26.2;q22) abnormality, which is commonly seen in therapy-related AML.

Patients previously diagnosed with AML may indeed acquire an inv(3)(q21q26.2) or t(3;3)(q21;q26.2), which in such case may indicate an accelerated or aggressive blast phase of their clinical course. In a study of 18 patients, 15 died within 10 months of diagnosis. Three of three patients with bone marrow transplantation and aggressive chemotherapy still suffered early relapses. Ultimately, this form of AML carries a poorer prognosis and a shorter survival.


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Contributed by Milon Amin, MD and Raymond E. Felgar, MD

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