t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.
BACKGROUND
The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1.


METHODS
The current study describes what to the authors' knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)-associated leukemias, in which 24 cases arose after chemotherapy. Conventional G-band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing.


RESULTS
In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)-associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5-fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT-PCR followed by DNA sequencing showed that the AML1-/MDS1-/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow-up.


CONCLUSIONS
Activation of AME through t(3;21) defines a highly aggressive, therapy-related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause.
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
C Cameron
CC
Yin
Jorge
J
Cortes
Bedia
B
Barkoh
Kimberly
K
Hayes
Hagop
H
Kantarjian
Dan
D
Jones
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001853:Bone Marrow / Q000473:pathology; D002891:Chromosomes, Human, Pair 21 / Q000187:drug effects*; D002893:Chromosomes, Human, Pair 3 / Q000187:drug effects*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects*; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000032:analysis* / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D014157:Transcription Factors; D006918:Hydroxyurea