Final Diagnosis -- Acute Myelogenous Leukemia


  MEGAKARYOCYTIC DYSPLASIA WITH AN ABNORMAL KARYOTYPE: 46,XY,inv(3)(q21q26)[17],-7[3][cp17]/46,XY[2]


The present case provides an example of acute myelogenous leukemia with the clinical and histologic picture associated with inv(3)(q21q26), a chromosomal abnormality that has important prognostic and therapeutic implications. The association between AML and either paracentric inversions or translocations was first described in 1982 and 1976 respectively (1,2). Since these initial case reports, greater than 140 cases of abnormalities involving the 3q21 and 3q26 bands have been described in a variety of hematopoietic abnormalities including myeloproliferative and myelodysplastic syndromes (MDS)(3,4). Hematologic findings associated with these cytogenetic abnormalities include a myelodysplastic syndrome which precedes the development of AML, a normal to elevated platelet count, and a high frequency of trilineage dysplasia, particularly involving the megakaryocytic lineage, features which are similar to those described with the 5q minus syndrome (5,14,15). Cytogenetics provides important prognostic information in these cases, because unlike the favorable prognosis associated with 5q minus syndrome, patients with abnormalities of the long arm of chromosome 3 tend to have an aggressive disease which rapidly progresses from MDS to AML, and has a poor response to conventional induction chemotherapy, and in associatd with shortened survival (5,6,15).

Whereas the clinical picture associated with inv(3)(q21q26) has several common features, the leukemias associated with this karyotype vary widely. The FAB classification of the AML in the present case was M0, based upon the myeloid lineage, as established by the flow cytometric immunophenotypic studies, combined with the lack of staining (<3% of blasts staining) with either sudan black or myeloperoxidase (7). Although the increased numbers of dysplastic megakaryocytes raised the possibility of a FAB-M7 subtype, markers of megakaryocytic differentiation were not present on the blasts by either immunohistochemical or flow cytometric methods. The presence of CD7 on the blast population, which is not uncommon among AML (8), along with the positive CD34, CD13,33, and HLA-DR (data not shown) is consistent with the reported immunophenotype of inv(3)(q21q26) associated AML (5).

While this case provides an example of the clinical and histologic features associated with inv(3)(q21q26), there remain several unresolved issues with regard to the present case as well as the purported clinical entity of inv(3)(q21q26) syndrome. The finding of monosomy 7 in a subset of cells karyotyped raises the question of what role, if any, this chromosomal abnormality played in the this patient's disease. Monosomy 7 is a well-known cytogenetic abnormality associated with MDS and total or partial monosomy 7 has been frequently associated with inv(3)(q21q26) (10, 14). The finding of monosomy 7 in 3 of the 20 metaphase spreads analyzed raises the question of whether this abnormality played a role in this patient's hematologic picture or was simply an in vitro artifact resulting from random chromosomal loss. Interphase fluorescent in-situ hybridization (FISH), a procedure that could address the issue of non-random monosomy 7, was not performed.

A final unresolved issue concerns the molecular mechanism behind the generation of the clinical picture associated with inv(3)(q21q26). In light of the extensive abnormalities observed in the megakaryocytic lineage and its mapping to chromosome 3 band q26.33q27, the thrombopoetin gene was considered a prime candidate for playing an important role in the MDS/AML process (9). However, preliminary studies have failed to show transcriptional activation of this gene associated with inv(3)(q21q26) leukemia cells (9). More recent work has implicated the aberrant expression of the human ectotropic virus integration site-1 gene (EVI-1) as a potential player in leukemogenesis (11; Figure 26 from reference 11). EVI-1, located on chromosome 3 q26, is a sequence-specific DNA-binding protein that has been shown to be expressed in a variety of tissues. EVI-1 is not normally expressed in hematopoietic tissues. In addition, the C-terminus of EVI-1 may also be expressed as a fusion protein with N-terminus of MDS-1, the gene lying immediately telomeric to EVI-1 on chromosome 3, creating a protein with markedly different DNA-binding characteristics (12). Studies in both human and murine leukemia have shown aberrant expression of EVI-1 (11). Over-expression may occur through two mechanisms including chromosomal rearrangements resulting in over-expression of wild type EVI-1 or generating novel fusion proteins with TEL or AML1, two proteins well known to be involved in leukemogenesis (13). The other mechanism, retrovirallymediated over-expression of EVI-1, has been described in murine but not human leukemias (11). The role of the q21 locus plays in the development of leukemia is yet undetermined. The enhancer of the ribophorin gene, which is located at 3q21, has been hypothesized to function as a trans-acting element which drives the inappropriate expression of EVI-1 in cases of hematopoietic disturbances involving chromosomal rearrangements (Figure 26, from reference 11). However, since multiple genes map to this region of chromosome 3, the role of the ribophorin gene in the development of leukemia is speculative at this time.

In summary, this 66-year-old male had a MO AML in the background of marked megakaryocytic dysplasia. The cytogenetic studies identified an abnormal karyotype containing inv(3)(q2lq26) which provided important information allowing the differentiation of this patient's disease, which tends to exhibit an aggressive course with poor response to induction chemotherapy, and 5q minus syndrome, a disease that may have a similar clinical and histologic picture as seen in this case, but tends to have a more indolent course.


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Contributed by Scott M. Kulich, MD, PhD, Sofia Shekhter-Levin, MD, PhD, and David Bahler, MD, PhD


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