Hematopathology / t(3;21)-Associated t-MDS/AML
Myelodysplastic Syndrome/Acute Myeloid Leukemia
With t(3;21)(q26.2;q22) Is Commonly a Therapy-Related
Disease Associated With Poor Outcome
Shaoying Li, MD, C. Cameron Yin, MD, PhD, L. Jeffrey Medeiros, MD, Carlos Bueso-Ramos, MD, PhD,
Gary Lu, MD, and Pei Lin, MD
Key Words: Therapy-related MDS/AML; Myelodysplastic syndrome; Acute myeloid leukemia; t(3;21)(q26.2;q22); inv(3)/t(3;3)
DOI: 10.1309/AJCPZRRL2DGC2ODA
CME/SAM
Upon completion of this activity you will be able to:
• define the clinicopathologic and cytogenetic features of
myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)
associated with t(3;21)(q26.2;q22).
• compare the clinicopathologic and prognostic features of MDS/AML
associated with t(3;21)(q26.2;q22) with MDS/AML associated with
inv(3)(q21q26.2) or t(3;3)(q21;q26.2).
• identify the distinct features of t(3;21)-associated therapy-related
MDS/AML in comparison to other therapy-related MDS/AML in
general.
Abstract
The t(3;21)(q26.2;q22) translocation is rare in
cases of myelodysplastic syndrome (MDS) and acute
myeloid leukemia (AML). We studied 17 patients with
MDS/AML associated with t(3;21) and compared
them with 17 patients with MDS associated with inv(3)
(q21q26.2)/t(3;3)(q21;q26.2), because these entities
share 3q26 locus abnormalities. The t(3;21) group
included 9 men and 8 women, with a median age of
62 years (range, 13-81 years). One case was de novo
AML and 16 cases were therapy-related, including 12
MDS (blasts, <15%) and 4 AML (blasts, 33%-50%).
All patients had multilineage dysplasia, whereas none
had thrombocytosis. Additional cytogenetic aberrations
were identified in 12 cases, including –7/7q (n = 9)
and a complex karyotype (n = 7). All patients died,
with 1- and 2-year survival rates of 35% and 6%,
respectively. Although multilineage dysplasia and
frequent association with –7/7q were similar in both
groups, MDS/AML cases associated with t(3;21) have a
higher frequency of therapy-related disease and shorter
survival times, suggesting that they are distinct from
MDS/AML cases associated with inv(3)/t(3;3).
146 Am J Clin Pathol 2012;138:146-152
146 DOI: 10.1309/AJCPZRRL2DGC2ODA
The ASCP is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.
The ASCP designates this journal-based CME activity for a maximum of 1
AMA PRA Category 1 Credit ™ per article. Physicians should claim only the
credit commensurate with the extent of their participation in the activity.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016
This activity qualifies as an American Board of Pathology Maintenance of
Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 161. Exam is located at www.ascp.org/ajcpcme.
Disruption of chromosome locus 3q26 is a rare but
recurrent cytogenetic aberration that occurs in acute myeloid
leukemia (AML) or myelodysplastic syndrome (MDS). Chro-
mosome 3q26.2 abnormalities have been shown to acti-
vate EVI1 expression, in at least a subset of cases, and
EVI1 plays an important role in pathogenesis by promoting
myeloid proliferation and blocking differentiation. Among
several types of 3q26 aberrations, the most common are inv(3)
(q21q26.2)/t(3;3)(q21;q26.2) and t(3;21)(q26.2;q22), as seen
in 22% and 7% of cases, respectively.
AML associated with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)
is recognized as a distinct entity in the 2008 World Health
Organization (WHO) classification, included within the group
of AML with recurrent genetic abnormalities.1 These patients
often present with anemia and the platelet count can be normal
or increased. The bone marrow typically shows increased small
hypolobated megakaryocytes and multilineage dysplasia. These
patients are frequently refractory to conventional chemotherapy
regimens and have a short overall survival.2,3
A small subset of MDS cases also are associated with
inv(3)/t(3;3). Affected patients share many features with
patients with AML associated with inv(3)/t(3;3) and in such
patients, the disease has a propensity to progress rapidly to
AML. We suggested previously that these patients with MDS
are part of the spectrum of myeloid neoplasms associated with
inv(3)/t(3;3).
By contrast, t(3;21)(q26.2;q22), reported in approxi-
mately 1% of MDS/AML cases, is less well understood. The
pathologic features of these neoplasms are not well described
and prognostic data are rarely available.4-10 The cytogenetic
© American Society for Clinical Pathology

abnormality involves 3q26.2, in common with inv(3)/t(3;3),
therefore one might hypothesize that MDS/AML cases associ-
ated with these cytogenetic abnormalities are closely related,
but few studies have addressed this issue in the literature.
In this study, we report the clinicopathologic and cyto-
genetic features of a group of 17 patients with MDS or AML
associated with t(3;21)(q26.2;q22). We further compare the
clinicopathologic and prognostic features of this group with
those of a group of 17 patients with MDS associated with
inv(3)(q21q26.2) or t(3;3)(q21;q26.2). Lastly, we discuss the
distinct features of t(3;21) cases in comparison with other
therapy-related MDS/AML in general.
Materials and Methods
We searched the files of the Department of Hematopa-
thology at The University of Texas MD Anderson Cancer
Center for myeloid neoplasms with disruption of chromo-
some 3q26.2 detected by conventional cytogenetic analysis.
The study period was October 1997 through June 2011.
A total 17 cases of either MDS or AML associated with
t(3;21)(q26.2;q22) were identified. The medical records of
each case were reviewed. We compared this group with 17
MDS patients who had inv(3)(q21q26.2) or t(3;3)(q21;q26.2)
examined from October 1997 to August 2007 and described
previously.11 This study was performed with the approval of
the institutional review board of our institution.
Bone marrow aspirate smears and biopsy touch imprint
slides were air-dried and stained with Wright-Giemsa. Bone
marrow biopsy and aspirate clot specimens were fixed in for-
malin and 4-μm thick slides were stained with H&E. Slides
were reviewed to confirm the diagnosis, and the neoplasms
were classified according to the 2008 WHO scheme, incorpo-
rating the ancillary data.
Bone marrow aspirate specimens were prepared for
conventional cytogenetic analysis using methods described
previously.12 Metaphases were banded by the standard GTG
method. The karyotypes were reported according to the 2009
International System for Human Cytogenetic Nomenclature.13
A subset of cases was assessed for RAS and/or FLT3/ITD or
FLT3/D835 mutations using methods previously described.14,15
In 2 cases with available RNA, EVI1 expression was quantified
by real-time polymerase chain reaction (PCR) using primers
that cover exon I of EVI1 gene: forward primer, TTGCCAAG-
TAACAGCTTTGCTG; reverse primer, CCAAAGGGTC-
CGAATGTGACTT, and SYBR Green (Applied Biosystems,
Foster City, CA)–based detection method.
Overall survival was calculated from date of diagnosis of
either MDS or AML associated with t(3;21)(q26;q22) until
date of death. Patient survival was analyzed using the Kaplan-
Meier method and compared using the double-sided log-rank
test (Mantel-Cox). Fisher exact test was used to analyze the
© American Society for Clinical Pathology
Hematopathology / Original Article
differences between the 2 groups of patients. GraphPad Prism
5 (GraphPad Software Inc, La Jolla, CA) was used for statisti-
cal analysis. P < .05 was considered statistically significant.
Results
Clinical and Pathologic Features
We identified 17 patients with AML or MDS associated
with t(3;21)(q26.2;q22). Sixteen patients had therapy-related
MDS (t-MDS; n = 12) or AML (t-AML; n = 4) and 1 patient
had de novo AML. The clinical and pathologic features of
these patients are summarized in ❚Table 1❚.
Patients included 9 men and 8 women with a median age
of 62 years (range, 13-81 years). All had anemia with a median
hemoglobin level of 9.5 g/dL (95 g/L; range 8.0-12 g/dL [80-
Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016
120 g/L]; reference range, 14-18 g/dL [140-180 g/L]); 16
patients had thrombocytopenia, with a median platelet count of
26 × 103/μL (26 × 109/L; range, 4-90 × 103/μL [4-90 × 109/L];
reference range, 140-440 × 103/μL [140-440 × 109/L]); and
8 patients had leukopenia with a median leukocyte count of
2,500/μL (2.5×109/L; range, 1,500-3,700/μL [1.5-3.7 × 109/L];
reference range, 4,000-11,000/μL [4-11 × 109/L]).
Bone marrow aspirate smears in all cases showed dys-
plasia involving the erythroid and/or myeloid lineages ❚Image
1B❚. Fifteen (88%) of 17 cases showed megakaryocytic hypo-
plasia. Small hypolobated megakaryocytes, as seen typically
in cases of MDS or AML associated with inv(3)/t(3;3), were
observed in 4 of 5 cases evaluable in this cohort ❚Image 1A❚,
with only 1 case showing an increased number of megakaryo-
cytes. The other 12 cases showed severe megakaryocytic
hypoplasia precluding adequate morphologic assessment. The
bone marrow blast count ranged from 1% to 15% in cases
of t-MDS and 33% to 50% in t-AML. Bone marrow biopsy
specimens were hypocellular in 7 cases, normocellular in 4
cases, and hypercellular in 1 case of t-MDS. Three t-AML
cases were normocellular and 1 was hypocellular. The de
novo AML case had evidence of granulocytic and megakaryo-
cytic dysplasia in a hypercellular bone marrow.
The morphologic features of these cases are not specific.
Although all MDS cases were classified as therapy-related,
according to WHO classification criteria, the morphologic
features were similar to refractory anemia, refractory cyto-
penia with multilineage dysplasia, or refractory anemia with
excess blasts. Similarly, all AML cases except 1 were therapy-
related, and were classified as such, but showed minimal,
granulocytic, or myelomonocytic differentiation. One case
was associated with 66% erythroblasts and met criteria for
acute erythroid leukemia. Using the older French-American-
British classification, the AML cases would be classified as
M0, M1, M2, M4, or M6. No cases in this study had M3, M5,
or M7 morphologic characteristics.
Am J Clin Pathol 2012;138:146-152 147
147 DOI: 10.1309/AJCPZRRL2DGC2ODA 147
Li et al / t(3;21)-Associated t-MDS/AML

❚Table 1❚
Clinical Features of 17 Cases of MDS/AML Associated With t(3;21)(q26.2;q22)

Latency: Interval
Age (y)/ Primary Primary to from MDS
No Sex Tumor Therapy for Primary Tumor MDS (mo) to AML (mo)

1 32/F DLBCL Anthracyclines, alkylating agents, SCT-auto 52.3 2.1

2 71/F DLBCL CHOP, paclitaxel, topotecan, rituximab, radiation ,SCT-auto 20.0
3 65/F FL CHOP, bleomycin, MINE, ESHAP, FMD 61.6
4 56/F FL CHOP, MINE, ESHAP, paclitaxel, fludarabine. and rituximab 20.2*
5 29/M B-cell NHL COPADM, ifosfamide, etoposide 35.5
6 49/M CHL-NS MOPP-ABVD 25.2 3.1
7 81/M Myeloma Bortezomib, cyclophosphamide, melphalan, prednisone 31.2
8 13/F T-ALL Chemotherapy, regimen unknown 63.9 15.8
9 57/F AML M2 Topotecan, cyclophosphamide, tretinoin, cytarabine, daunorubicin 40.7 14.9

10 44/M AML-M5a CAT, hydroxyurea, cytarabine 11.0 1.2

11 73/F Breast Ca Tamoxifen; FU, mitoxantrone, cyclophosphamide, paclitaxel 151.2
12 55/F Breast Ca FAC, SCT-auto, radiation, tamoxifen 39.1 2.6
13 62/M Breast Ca Surgery, FAC 42.5*
14 72/M Prostate Ca Radiation 9.2 3.2

15 78/M Prostate Ca Leuprolide, alternative medicine 19.0*

Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016

16 76/M Lung and prostate Ca VP-16, cisplatin, leuprolide, radiation 58.0*
17 68/M None

AML, acute myeloid leukemia; Ca, carcinoma; CAT, cyclophosphamide, Ara-C (cytarabine), and topotecan; CHL-NS, nodular sclerosis Hodgkin lymphoma; CHOP, cyclophos-
phamide, hydroxydaunomycin, vincristine (Oncovin), prednisone; COPADM, cyclophosphamide, Oncovin, prednisolone, doxorubicin (Adriamycin), methotrexate; DBVE,
doxorubicin, bleomycin, vincristine, etoposide; DLBCL, diffuse large B-cell lymphoma; ESHAP, etoposide, methylprednisolone (Solu-Medrol), Ara-C, cisplatin (Platinol);
FAC, 5-fluorouracil, Adriamycin, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; FL, follicular lymphoma; FMD, fludarabine, mitoxantrone, dexamethasone;
G-CSF, granulocyte colony-stimulating factor; MDS, myelodysplastic syndrome; MINE, mitoguazone, ifosfamide, vinorelbine, and etoposide; MOPP/ABVD, mechlor-
ethamine, Oncovin, procarbazine, prednisone/Adriamycin, bleomycin, vincristine, dacarbazine; NHL, non-Hodgkin lymphoma; SCT-allo, allogeneic stem cell transplantation;
SCT-auto, autologous stem cell transplantation; T-ALL, T-cell acute lymphoblastic leukemia.
* Primary to t-AML (no MDS).

For the group of patients with t-MDS or t-AML, the
interval from primary tumor to development of MDS/AML
associated with t(3;21) ranged from 9.2 to 151 months. The
primary tumors included non-Hodgkin lymphoma (n = 5),
acute leukemia (n = 3), breast carcinoma (n = 3), prostate
carcinoma (n = 2), classic Hodgkin lymphoma (n = 1),
plasma cell myeloma (n = 1), and 1 patient with concurrent
prostatic and lung carcinoma (Table 1). Each patient had
relapses or metastases and were treated with multiple cycles
of chemotherapy that spanned several years. The therapeutic

A B

❚Image 1❚ Morphologic features of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) with t(3;21)(q26.2;q22).
A, Corresponding bone marrow biopsy specimen from a patient with t-MDS/AML showing disorganized hematopoiesis
and hyperplasia of small hypolobated megakaryocytes (arrows) (H&E, ×200). B, Bone marrow aspirate smear showing
dyserythropoiesis (arrow) and increased blasts (arrowhead) (Wright-Giemsa stain, ×1,000).

148 Am J Clin Pathol 2012;138:146-152 © American Society for Clinical Pathology

148 DOI: 10.1309/AJCPZRRL2DGC2ODA
 Hematopathology / Original Article

cytogenetic aberrations. Monosomy 7/del(7q) was the most

common abnormality, present in 9 (53%) patients. Trisomy
8 was detected in 3 (18%) patients, monosomy 5 in 1 (6%)
Survival
Therapy for t-MDS/AML (mo) patient, and a complex karyotype in 7 (41%) patients. All
except one with complex cytogenetic findings also had –7/
G-CSF, CAT-G 3.5
Thalidomide and arsenic, bexarotene 13.6 del(7q).
Unknown 3.2 The t(3;21) and –7/7q were detected simultaneously in
Cyclosporin, fludarabine, cytarabine 0.2
G-CSF, supportive 18.6 7 patients and sequentially in 2 patients. In the 2 sequentially
Pravastatin, idarubicin, cytarabine 2.1 detected cases, detection of –7 preceded that of t(3;21) by
Decitabine 8.9
Decitabine 4.7
approximately 3 months, suggesting that t(3;21) evolved as a
Cytarabine, clofarabine, gemtuzumab ozogamicin, 28 secondary event. In 1 of these 2 patients, emergence of t(3;21)
fludarabine, SCT-allo was accompanied by a slight increase of bone marrow blasts,
Hydroxyurea, cytarabine, SCT-allo 5.7
Daunorubicin, topotecan 1.1 from 4% to 7%. Trisomy 8 was detected simultaneously with
Idarubicin, cidarubicin, cytarabine, SCT-allo 20.9 t(3;21) in 3 cases. RAS mutation (n = 6) and FLT3 (n = 3)
Cloretazine, hydroxyurea, clofarabine, idarubicin, cytarabine 4.2
Fludarabine, idarubicin, cytarabine, tretinoin, 18.3 mutations were not detected in all cases tested.
thalidomide, hydroxyurea Two cases analyzed for EVI1 expression by quantitative
Idarubicin, cytarabine, azacitidine, vorinostat, decitabine 21.2

Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016

Idarubicin, cytarabine 0.5 reverse transcriptase PCR showed increased expression of
Clofarabine 0.6 EVI1 (1-1.5 fold) compared with normal controls.

Comparison of Patients With MDS Associated With

agents used included idarubicin, doxorubicin, hydroxyurea,
topotecan, thalidomide, fludarabine, decitabine, clofarabine,
cytarabine, cyclophosphamide, and azacitidine. Three patients
underwent allogeneic stem cell transplantation.
Clinical follow-up showed that all patients died after
diagnosis of MDS or AML, with a median survival of 4.7
months (range, 0.2 to 28 months). In 7 of 12 patients with
t-MDS, the disease progressed to AML.
Conventional Cytogenetic and Molecular Findings
Cytogenetic results for the study group revealed iso-
lated t(3;21)(q26.2;q22) in 5 (29%) patients, including the
single case of de novo AML. Twelve patients had additional
t(3;21) vs MDS Associated With inv(3)/t(3;3)
We compared the clinicopathologic and cytogenetic
features of the study group with those of 17 patients with
MDS associated with inv(3)/t(3;3) ❚Table 2❚. Overall, t(3;21)
occurred almost exclusively in the therapy-related setting. In
contrast, inv(3)/t(3;3) cases occurred either de novo or after
therapy (n = 6) (P = .001). Small hypolobated megakaryo-
cytes were observed in MDS/AML associated with t(3;21),
as is common in inv(3)/t(3;3) cases of MDS/AML. However,
cases of MDS/AML associated with t(3;21) often showed
megakaryocytic hypoplasia, unlike inv(3)/t(3;3) cases that
commonly show megakaryocytic hyperplasia. The frequency
of –7/7q, –5/5q, or a complex karyotype was similar in both
groups (P = .3, .2, and .7, respectively).

❚Table 2❚
Comparison of Clinical Features of MDS/AML With t(3;21) vs MDS With inv(3)/t(3;3)

Features t(3;21) (n = 17) inv(3) or t(3;3) (n = 17)

De novo 1 11
Therapy related 16 6
Median (range) age, y 62 (13-81) 60 (15-77)
Male:Female ratio 9:7 9:8
Bone marrow morphology
Megakaryocytes Hypoplasia common, hyperplasia of small Hyperplasia common, small hypolobated
hypolobated forms rare forms common
Myeloid and erythroid dysplasia Common Common
Latency (mo): Primary to t-MDS/AML 9-151 22-156
Latency (mo): t-MDS to t-AML 1.2-15.8 8-11
Cytogenetics, No. (%) of cases
Isolated 3q26 5 (29) 4 (24)
–7/7q 9 (53) 12 (70)
–5/5q 1 (6) 5 (29)
Complex karyotype 7 (41) 5 (29)
Median survival (mo) 4.7 14

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; t, therapy related.

© American Society for Clinical Pathology Am J Clin Pathol 2012;138:146-152 149

149 DOI: 10.1309/AJCPZRRL2DGC2ODA 149
Li et al / t(3;21)-Associated t-MDS/AML

Overall survival was significantly shorter for patients with
MDS/AML associated with t(3;21) than with inv(3)/t(3;3)
(median, 4.7 vs 14 months, P = .03) ❚Figure 1A❚. This was
also true for cases that were therapy-related (median, 5.2 vs
17.5 months, P = .047) ❚Figure 1B❚. Survival of t-MDS/AML
patients with isolated t(3;21) was similar to that of patients
who had t(3;21) with other cytogenetic abnormalities includ-
ing –7/7q (P = .18) or a complex karyotype (P = .17) ❚Figure
1C❚ and ❚Figure 1D❚.
Discussion
t(3;21)(q26.2;q22) is a rare cytogenetic abnormality in
cases of MDS or AML, reported in approximately 1% of all
cases. Of the 143 hematopoietic neoplasms associated with
t(3;21)(q26.2;q22) listed in the Mitelman database,16 19 cases
were MDS ❚Table 3❚, with the remaining cases being either
MECOM, and the fusion products play a pivotal role in patho-
genesis of MDS and AML. The fusion products can block
myeloid differentiation, promote proliferation and malignant
transformation by exerting a dominant-negative effect over
RUNX1-induced normal transcriptional activation, antagonize
the growth-inhibitory effects of transforming growth fac-
tor, block JNK activity and therefore prevent stress-induced
apoptosis, and enhance AP-1 activity.17,18 We and others have
identified the presence of AML1/MDS1/EVI1 or other fusion
transcripts in myeloid neoplasms associated with t(3;21).5,6,8,19
In this study, we report clinicopathologic, cytogenetic,
and survival data for a large group of cases of MDS or AML
associated with t(3;21)(q26.2;q22). We also compared these
cases to the more common group of MDS/AML associated
with inv(3q21q26.2) or t(3;3)(q21;q26.2). Similar to other
MDS/AML cases with chromosome 3q26 locus abnormali-

Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016

AML or chronic myeloproliferative disorders in blast phase.
t(3;21) is thought to result in translocation and fusion of part of
the RUNX1 gene to MECOM (currently preferred designation
for the MDS-EVI1 gene locus) located in the 3q26 region. The
translocation is thought to aberrantly activate both RUNX1 and
ties, myeloid neoplasms associated with t(3;21) usually dis-
play marked dysplasia. Blasts can exhibit minimal, myeloid,
or monocytic differentiation and rarely these cases can mimic
acute erythroid leukemia. Small hypolobated megakaryocytes
are also noted. However, MDS/AML cases associated with
t(3;21) do have some features that distinguish them from

A B
100 100
Percent Survival
Percent Survival

50 50
inv(3)/t(3;3)
inv(3)/t(3;3)
t(3;21) t(3;21)

0 0
0 10 20 30 40 0 10 20 30 40
Time (mo) Time (mo)

C D
100 100
Percent Survival
Percent Survival

No –7/7q Noncomplex karyotype

50 50

–7/7q
Complex karyotype
0 0
0 10 20 30 0 10 20 30
Time (mo) Time (mo)

❚Figure 1❚ Overall survival. A, Comparison of all patients with myelodysplastic syndrome/acute myeloid leukemia (MDS/
AML) associated with t(3;21) (n=17) vs inv(3)/t(3;3) (n=17). Patients with myeloid neoplasms associated with t(3;21) had
significantly worse survival (P = .03). B, Comparison of therapy-related MDS/AML patients with t(3;21) (n=16) vs inv(3)/t(3;3)
(n = 6). Patients with therapy-related myeloid neoplasms associated with t(3;21) had significantly worse survival (P = .047). C,
Comparison of t(3;21)-associated MDS/AML with (n = 9) vs without (n = 8) additional –7/7q (P = .18). D, Comparison of patients
with t(3;21)-associated MDS/AML with (n = 7) vs without (n = 10) a complex karyotype (P = .17).

150 Am J Clin Pathol 2012;138:146-152 © American Society for Clinical Pathology

150 DOI: 10.1309/AJCPZRRL2DGC2ODA
 Hematopathology / Original Article

❚Table 3❚
Characteristics of 19 MDS Cases Associated With t(3;21) From the Mitelman Database

Age (y)/Sex Primary Tumor Treatment for Primary MDS Cytogenetics

13/F Unknown NOS 46,XX,t(3;21)(q26;q22)

48/F Unknown NOS 46,XX,t(3;21)(q26;q11),del(7)(p11p22)
50/M Unknown NOS 46,XY,t(3;21)(q26;q22)/47,idem,+13/46,XY,i(17)(q10)
?/F Unknown RA 46,XX,t(3;21)(q26;q21),del(7)(q31q34)
15/F Unknown RAEB-2 46,XY,t(3;21)(q26;q21)/47,idem,+12
74/F Unknown NOS 46,XX,t(3;21)(q26;q22)/46,idem,add(5)(q31)
64/F Unknown RAEB 45,XX,t(3;21)(q26;q22),–7
64/M Unknown RAEB-2 46,XY,t(3;21)(q26;q22)
?/F Unknown NOS 46,XX,t(3;21)(q26;q22)
44/M CML Chemo and R NOS 46,XY,del(1)(p3?2),t(3;21)(q26;q22),der(20)t(1;20)(p3?;q11)
49/F B-cell lymphoma Chemo RAEB 45,XX,t(3;21)(q26;q22),–7
49/F Lung Ca Chemo NOS 45,XX,t(3;21)(q26;q22),–7
54/F Breast Ca Chemo NOS 46,XX,t(3;21)(q26;q22),del(7)(q22)
59/F Myeloma Chemo and R RA 43,X,-X,t(3;21)(q26;q22),del(4)(p14p16),-6,-8,del(10)(p11), der(12
t(1;12)(q21;p12),–13,–14,–14,del(20)(p12),add(22)(q12),+3mar
71/F Ovarian Ca Chemo RAEB-1 46,XX,t(3;21)(q26;q22)
65/F Breast Ca Chemo RAEB-2 46,XX,t(3;21)(q26;q22)
32/M cHL Chemo RAEB-2 46,XY,t(3;21)(q26;q22),del(5)(q13q34)/46,XY,t(3;21),–5,+mar

Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016

52/M cHL Chemo and R RAEB-1 46,XY,t(3;21)(q26;q22),add(7)(q21)
44/F cHL Chemo and R RAEB 45,X,–X,t(3;21)(q26;q22),del(5)(q13q31)

Ca, carcinoma; Chemo, chemotherapy; cHL, classical Hodgkin lymphoma; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; NOS, myelodysplastic
syndrome not otherwise specified; R, radiation therapy; RA, refractory anemia; RAEB, refractory anemia with excess blast.

MDS/AML associated with inv(3)/t(3;3). In our experience,
MDS/AML associated with t(3;21) occurs almost exclusively
in the therapy-related setting, and commonly shows mega-
karyocytic hypoplasia, unlike the megakaryocytic hyperpla-
sia usually present in cases of MDS/AML associated with
inv(3)/t(3;3). No patients with t(3;21)-associated MDS/AML
had thrombocytosis and only rarely did patients have a normal
platelet count. Affected patients also had a very short overall
survival (median, 4.7 months). Our results suggest that MDS/
AML associated with t(3;21) is a particularly poor prognos-
tic subset that needs to be distinguished from other cases of
MDS/AML associated with 3q26 abnormalities. This result
differs from that reported by Lugthart and colleagues20 who
observed better survival for patients with AML with t(3;21)
than those with inv(3)/t(3;3).
Lymphoid neoplasms or breast cancers are usually the
primary tumors in patients with t-MDS/AML in general,
accounting for about 35% and 24% of cases, respectively.21
In this study of 16 patients with t-MDS/AML carrying t(3;21),
6 (38%) were previously treated for lymphoma and 3 (19%)
for breast cancer. When we compared these cases with the 6
cases of t-MDS/AML carrying inv(3)/t(3;3) in this study, we
found that the latter group occurred more commonly in patients
treated for lymphomas (5 [83%] of 6). t-MDS/AML associated
with t(3;21), in contrast, occurred in patients with a wider spec-
trum of tumors including lymphomas, leukemias, plasma cell
myeloma, and solid tumors. Obviously the small sample size
precludes definite conclusions. However, one can speculate that
differences in chemotherapeutic regimens used to treat patients
with lymphoma compared with those with other tumors may
predispose patients to either inv(3)/t(3;3) or t(3;21).
Two categories of t-MDS/AML are well recognized.
Those associated with unbalanced loss of genetic material,
including chromosomes 5 and/or 7 are usually associated
with exposure to alkylating agents, whereas balanced chro-
mosomal translocations are typically associated with expo-
sure to inhibitors of DNA topoisomerase II.22 The former
has a latency period of 5 to 10 years compared with 1 to 5
years in the latter group after treatment of primary tumors.
However, most patients usually are treated with both types of
agents and a distinction cannot be made easily. In fact, most
patients in the study group received both alkylating agents and
DNA topoisomerase II inhibitors for their primary tumors.
In addition to the balanced t(3;21), deletion of 7/7q, +8 and/
or a complex karyotype occurred in 53%, 18%, and 41%
of cases, respectively. The latency interval from the time of
primary malignancy to the onset of t-MDS/AML in this study
group also followed the general patterns described for the 2
categories of t-MDS/AML spanning from 9.2 months to 151
months. Stein et al23 suggested that development of mono-
somy 7 may result from EVI1 activation-induced genomic
instability. However, monosomy 7 occurred before the t(3;21)
in 2 cases of our study arguing against this hypothesis. It is not
clear from our results what general type of therapy is associ-
ated with genesis of t(3;21).
Therapy-related myeloid neoplasms, in general, have a
poor prognosis, with 5-year survival rates of less than 10%. It
is believed that patients with balanced translocations usually
have a better prognosis, whereas patients with chromosome
7 abnormalities or a complex karyotype have a particularly
poor prognosis, with a median survival of less than 1 year.22
Similarly, in this study, 65% of our patients died within 1 year

© American Society for Clinical Pathology Am J Clin Pathol 2012;138:146-152 151

151 DOI: 10.1309/AJCPZRRL2DGC2ODA 151
Li et al / t(3;21)-Associated t-MDS/AML
and all patients died within 2 years and 4 months. However, a
finding unique to our patients was that regardless of whether
the chromosomal aberration identified was an isolated t(3;21)
or a complex karyotype, all our patients had a poor prognosis,
indicating t(3;21) alone was a significant adverse factor.
In summary, we have described 17 patients with either
MDS or AML associated with t(3;21)(q26.2;q22). These
tumors share some similarity with cases of MDS/AML associ-
ated with inv(3q21q26.2) or t(3;3)(q21;q26.2). In particular,
cases of MDS/AML associated with t(3;21) usually show
marked multilineage dysplasia and frequent association with
–7 and a complex karyotype. However, unlike cases associated
with inv(3)/t(3;3), cases of MDS/AML associated with t(3;21)
occur almost exclusively after chemotherapy and are associated
with a very poor prognosis. We therefore conclude that MDS/
AML associated with t(3;21)(q26.2;q22) is a distinct entity.
From the Department of Hematopathology, The University of
Texas MD Anderson Cancer Center, Houston, Texas.
Address reprint requests to Dr Lin: Department of
Hematopathology, Unit 72, The University of Texas MD Anderson
Cancer Center, Houston, TX 77030; peilin@mdanderson.org.
References
1. Arber DA, Vardiman JW, Brunning RD, et al. Acute myeloid
leukemia with recurrent genetic abnormalities. In: Swerdlow
SH, Campo E, Harris NL, et al, eds. WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues. 4th ed.
Lyon, France: IARC Press; 2008:116-117.
2. Testoni N, Borsaru G, Martinelli G, et al. 3q21 and 3q26
cytogenetic abnormalities in acute myeloblastic leukemia:
biological and clinical features. Haematologica. 1999;84:690-
694.
3. Weisser M, Haferlach C, Haferlach T, et al. Advanced age
and high initial WBC influence the outcome of inv(3)
(q21q26)/t(3;3)(q21;q26) positive AML. Leuk Lymphoma.
2007;48:2145-2151.
4. Lo Coco F, Pisegna S, Diverio D. The AML1 gene: a
transcription factor involved in the pathogenesis of myeloid
and lymphoid leukemias. Haematologica. 1997;82:364-370.
5. Mitani K, Ogawa S, Tanaka T, et al. Generation of the
AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes
blastic crisis in chronic myelocytic leukemia. EMBO J.
1994;13:504-510.
6. Motomura S, Fujisawa S, Tsunooka S, et al. Translocation
(3;21)(q26;q22) in de novo acute myelogenous leukemia.
Leukemia. 1997;11:172-173.
7. Nucifora G, Begy CR, Erickson P, et al. The 3;21
translocation in myelodysplasia results in a fusion transcript
between the AML1 gene and the gene for EAP, a highly
conserved protein associated with the Epstein-Barr virus
small RNA EBER 1. Proc Natl Acad Sci U S A. 1993;90:7784-
7788.
8. Nucifora G, Begy CR, Kobayashi H, et al. Consistent
intergenic splicing and production of multiple transcripts
between AML1 at 21q22 and unrelated genes at 3q26 in
(3;21)(q26;q22) translocations. Proc Natl Acad Sci U S A.
1994;91:4004-4008.
152 Am J Clin Pathol 2012;138:146-152
152 DOI: 10.1309/AJCPZRRL2DGC2ODA
9. Chen Z, Morgan R, Baer MR, et al. Translocation (3;21)
characterizes crises in myeloid stem cell disorders. Cancer
Genet Cytogenet. 1991;57:153-159.
10. Pedersen-Bjergaard J, Johansson B, Philip P. Translocation
(3;21)(q26;q22) in therapy-related myelodysplasia following
drugs targeting DNA-topoisomerase II combined with
alkylating agents, and in myeloproliferative disorders
undergoing spontaneous leukemic transformation. Cancer
Genet Cytogenet. 1994;76:50-55.
11. Cui W, Sun J, Cotta CV, et al. Myelodysplastic syndrome
with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) has a high risk
for progression to acute myeloid leukemia. Am J Clin Pathol.
2011;136:282-288.
12. Onciu M, Schlette E, Medeiros LJ, et al. Cytogenetic findings
in mantle cell lymphoma cases with a high level of peripheral
blood involvement have a distinct pattern of abnormalities.
Am J Clin Pathol. 2001;116:886-892.
13. Shaffer LG, Slovak ML, Campbell LJ, eds. ISCN: An
International System for Human Cytogenetic Nomenclature
(2009). Basel, Switzerland: Karger; 2009.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on October 21, 2016
14. Hirsch-Ginsberg C, LeMaistre AC, Kantarjian H,
et al. RAS mutations are rare events in Philadelphia
chromosome-negative/bcr gene rearrangement-negative
chronic myelogenous leukemia, but are prevalent in chronic
myelomonocytic leukemia. Blood. 1990;76:1214-1219.
15. Lin P, Jones D, Medeiros LJ, et al. Activating FLT3
mutations are detectable in chronic and blast phase of
chronic myeloproliferative disorders other than chronic
myeloid leukemia. Am J Clin Pathol. 2006;126:530-533.
16. Mitelman F, Johansson B, Mertens F, eds. Mitelman Database
of Chromosome Aberrations and Gene Fusions in Cancer
(2011). Available at http://cgap.nci.nih.gov/Chromosomes/
Mitelman. Accessed June 7, 2011.
17. Goyama S, Kurokawa M. Pathogenetic significance
of ecotropic viral integration site-1 in hematological
malignancies. Cancer Sci. 2009;100:990-995.
18. Mitani K. Molecular mechanisms of leukemogenesis by
AML1/EVI-1. Oncogene. 2004;23:4263-4269.
19. Yin CC, Cortes J, Barkoh B, et al. t(3;21)(q26;q22)
in myeloid leukemia: an aggressive syndrome of blast
transformation associated with hydroxyurea or antimetabolite
therapy. Cancer. 2006;106:1730-1738.
20. Lugthart S, Groschel S, Beverloo HB, et al. Clinical,
molecular, and prognostic significance of WHO type
inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q
abnormalities in acute myeloid leukemia. J Clin Oncol.
2010;28:3890-3898.
21. Leone G, Fianchi L, Voso MT. Therapy-related myeloid
neoplasms. Curr Opin Oncol. 2011;23:672-680.
22. Vardiman JW, Arber DA, Brunning RD, et al. Therapy-
related myeloid neoplasms. In: Swerdlow SH, Campo E,
Harris NL, et al, eds. WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France:
IARC Press; 2008:127-129.
23. Stein S, Ott MG, Schultze-Strasser S, et al. Genomic
instability and myelodysplasia with monosomy 7 consequent
to EVI1 activation after gene therapy for chronic
granulomatous disease. Nat Med. 2010;16:198-204.
© American Society for Clinical Pathology