Cancer Genetics

Case Report
Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-MECOM
positive acute myeloid leukemia with subsequent emergence of a rare
KMT2A-ASXL2 fusion

a b s t r a c t
Secondary acquisition of t(9;22)(q34;q11.2)/BCR-ABL1 fusion in the context of de novo acute myeloid
leukemia (AML) with inv(3)(q21q26)/GATA2-MECOM rearrangement has been rarely reported. Further￾more, t(2;11)(p23;q23)/KMT2A-ASXL2 fusion has been rarely described with only a single case reported
to date. We report a 45-year-old male with a diagnosis of de novo AML harboring GATA2-MECOM rear￾rangement in conjunction with a related subclone with concomitant inv(3) and t(9;22). The patient was
treated with a tyrosine kinase inhibitor (TKI) which lead to disappearance of the inv(3)/t(9;22) subclone
and subsequent expansion of the inv(3) ancestral clone. The patient was started on a 7+3 induction reg￾imen with TKI but had persistent disease. He was placed on several additional treatment protocols and
only achieved morphologic remission with a combination of fludarabine, cytarabine and filgrastim with
TKI. Approximately 11.5 months after diagnosis the patient relapsed with the inv(3) clone predominating
initially, followed by return of the inv(3)/t(9;22) subclone and the emergence of a second subclone with
concomitant inv(3) and t(2;11)(p23;q23). Mate-pair sequencing was performed and identified a KMT2A￾ASXL2 in-frame fusion, which was only recently described in a single case of therapy-related AML. For
BCR-ABL1 positive AML, which generally carries a poor prognosis, treatment with TKIs has been proposed
in combination with standard chemotherapy. In our case, treatment with TKI alone led to initial response
of the BCR-ABL1 positive clone, but the ancestral clone quickly expanded and subsequent standard AML
therapy may have led to further clonal evolution and re-emergence of the BCR-ABL1 clone in the absence
of therapeutic selection.

BCR-ABL1 fusion is the genetic hallmark of chronic myeloid
leukemia (CML) and can also be observed in B-lymphoblastic
leukemia/lymphoma, mixed phenotype acute leukemias and acute
myeloid leukemia (AML) [1,2]. BCR-ABL1 is the primary driver in
CML and is the only cytogenetic feature observed in 80-90% ofcases in chronic phase [3]. In accelerated phase, CML can developadditional chromosomal abnormalities including inv(3)/t(3;3)resulting in GATA2-MECOM rearrangement, which can increase therisk of progression to blast phase and is associated with reducedresponse to tyrosine kinase inhibitors (TKI) [3]. Approximately 3%of de novo AML cases are BCR-ABL1 positive; however, acquisitionof BCR-ABL1 as a secondary abnormality in AML is rare, and hasbeen reported in the setting of myelodysplasia-related changes dueto therapy-related changes, or in relapsing disease including a fewcases described following hematopoietic transplantation [1,4,5].BCR-ABL1 positive AML is classified as high-risk and generally


carries a poor prognosis, however the overall clinical course
appears to be heavily dependent on the other co-occurring cy￾togenetic abnormalities and mutations. Acquisition of a related
subclone with a rare KMT2A rearrangement in the context of
acquired, secondary BCR-ABL1 positive AML is highly unusual and
has not been previously reported to our knowledge.
In this report, we describe a 45-year-old patient who pre￾sented with de novo inv(3)/GATA2-MECOM positive AML in conjunction with a related subclone with inv(3) and t(9;22). The patient was initially treated with single agent tyrosine kinase in￾hibitor (TKI) which led to an brief initial response, followed by
relapse with the insensitive ancestral inv(3) clone predominat￾ing. The patient was then treated with standard induction therapy
with TKI and had progressive disease. Several other chemotherapy
regimens were initiated, with only transient morphologic remis￾sion achieved while on a combination regimen consisting of flu￾darabine, cytarabine and filgrastim and TKI. At his most recent
relapse (11.5 months post diagnosis), the two clones present at
diagnosis re-emerged along with an additional related subclone
with inv(3) and t(2;11)(p23;q23). Mate-pair sequencing (MPseq)
was performed and revealed a rearrangement between KMT2A and
the ASXL2 gene, a haploinsufficient tumor suppressor that is recur￾rently mutated in t(8;21)(q22;q22)/RUNX1-RUNX1T1 AML [6,7]. The
KMT2A-ASXL2 fusion has only recently been described in a single
case of therapy-related AML (t-AML), and while the clinical signif￾icance of this rare fusion is unclear, the presence of a KMT2A re￾arrangement is generally an independent poor prognostic factor in
AML [8]. We provide a comprehensive description of the cytoge￾netic and molecular changes in this unusual case, and review sim￾ilar cases that may inform treatment andprognosis.
Materials and methods
Hematopathologic findings
A 45-year-old male presented with weakness and fatigue
and had microcytic anemia with marked thrombocytosis
(1,175 × 109/L; reference range: 150–375 × 109/L). At diagno￾sis, bone marrow core biopsy and aspirate were consistent with
AML (35% blasts by aspirate differential). A peripheral blood smear
showed 30% blasts with marked thrombocytosis and microcytic
anemia. The bone marrow biopsy showed 100% cellularity with
30–35% myeloblasts and flow cytometry initially confirmed in￾creased blasts (35%) expressing CD13, CD33, CD34, CD56 (partial),
HLA-DR (dim/partial), and CD45 (low density).
The most recent bone marrow biopsy and aspirate (~11.5
months post diagnosis) revealed a 30–40% cellular bone marrow
with increased immature cells. A peripheral blood smear was not
submitted for evaluation. The bone marrow aspirate differential
consisted of 31% blasts and 45% erythroid precursors. Flow cytom￾etry analysis of the bone marrow aspirate revealed an increased
blast gate (28.5%) with expression of CD4 (dim), CD13 and CD34.
Immunohistochemical studies performed on the clot and bone
marrow core biopsy revealed approximately 25% CD34 positive im￾mature cells.
Conventional chromosome analysis
Cells from the follow-up (non-diagnostic) bone marrow aspirate
specimens were cultured (24- and 48–h unstimulated), harvested,
and banded utilizing standard cytogenetic techniques according to
specimen-specific protocol.
Fluorescence in situ hybridization (FISH)
GATA2-MECOM (laboratory developed [9]) and BCR-ABL1 (Abbott
Molecular, Des Plaines, IL) dual-color dual-fusion (D-FISH) probe
sets, along with a KMT2A (Abbott Molecular) break-apart probe
(BAP) set were performed on the non-diagnostic bone marrow aspirate specimens. Five hundred interphase nuclei were analyzed
for each D-FISH probe set and 200 interphase nuclei were analyzed for the KMT2A BAP set. Cells from the bone marrow aspirate
were subjected to standard FISH pretreatment, hybridization, and
fluorescence microscopy according to specimen-specific laboratory protocols.
Molecular studies
Quantitative BCR-ABL1 mRNA analysis was evaluated using a
reverse transcription PCR-based assay that can detect both p190
and p210 fusion transcripts. A 42-gene next-generation sequenc￾ing (NGS) panel for hematologic neoplasms was performed on
the patient. The panels covers the following genes as well as se￾lect intronic regions including: ANKRD26, ASXL1, BCOR, CALR, CBL,
SMC3, SRSF2, STAG2, TERT, TET2, TP53, U2AF1, WT1 and ZRSR2. For
MPseq, DNA was processed using Illumina Nextera Mate Pair li￾brary kit (Illumina, San Diego, CA), multiplexed at two samples
per lane, and sequenced on the Illumina HiSeq 2500 on Rapid run
mode. Data were aligned to the reference genome (GRCh38) us￾ing BIMA V3, and abnormalities were identified and visualized us￾ing SVAtools and Ingenium, both in-house developed bioinformat￾ics tools [10,11].
Results and discussion
The diagnostic conventional chromosome study had been per￾formed at an outside institution and revealed inv(3)(q21q26.2) in
15 metaphases, inv(3) and t(9;22)(q34;q11.2) in four metaphases
and one normal metaphase (46,XY). At this time the patient was
started on imatinib (400 mg daily) and had a partial cytogenetic
response initially, but relapsed approximately three months later
with the inv(3) stemline clone (observed in all 20 metaphases an￾alyzed). FISH showed a GATA2-MECOM rearrangement in 74.6% of
interphase nuclei, while the BCR-ABL1 fusion was only observed
in 1.4% of interphase nuclei (abnormal cutoff: ≥0.6% of 500 in￾terphase cell analysis). An NGS 42-gene panel for myeloprolif￾erative disorders was performed and revealed pathogenic muta￾tions in GATA2 (NM_001145661.1, c.961C>T, p.Leu321Phe [MAF:
36%]), SF3B1 (NM_012433.2, c.1986C>A, p.His662Gln [37%]) and
WT1 (NM_024426.2, c.930_934dup, p.Arg312Leufs∗71 [13%]). The
patient was started on 7+3 induction therapy and had progres￾sive disease (Supplemental Fig. 1). He subsequently received ad￾ditional treatment regimens including mitoxantrone, etoposide,
intermediate-dose cytarabine (MEC) and TKI that was stopped due
to progressive disease, as well as fludarabine, cytarabine, filgras￾tim (FLAG) and TKI upon which he achieved morphologic re￾mission but was still positive for inv(3) by FISH and the p190
transcript by RT-PCR. At 5.5 months post diagnosis, conventional
chromosomes demonstrated re-emergence of the inv(3)(q21q26.2)
clone in 19 of 20 metaphases. He had one cycle of high-dose cy￾tarabine (HiDAC) as a bridge to haplo-identical donor stem cell
transplantation; however, he experienced progressive disease while
being worked up for transplant (Supplemental Fig. 1). Two cy￾cles of venetoclax and decitabine were administered with no re￾sponse. At this time conventional chromosome studies showed
eight metaphases with inv(3)(q21q26.2) (Fig. 1A), four with inv(3)
Please cite this article as: P.R. Blackburn, L. Huang and A. Dalovisio et al., Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-
MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion, Cancer Genetics, https://doi.org/10.
P.R. Blackburn, L. Huang and A. Dalovisio et al. / Cancer Genetics xxx (xxxx) xxx 3
JID: CGEN [m5G;January 2, 2020;10:1]
Fig. 1. Representative karyograms and interphase nuclei demonstrating the primary
clone and two related subclones. (A, B) Representative karyogram showing the pri￾mary clone with inv(3)(q21q26) and corresponding GATA2-MECOM rearrangement
demonstrated using the dual-color dual-fusion (D-FISH) probe set (arrows). (C, D)
Karyogram of the t(9;22)(q34;q11.2)/BCR-ABL1 positive subclone with inv(3) and
representative D-FISH image showing BCR-ABL1 fusion (arrows). (E, F) Karyogram of
the subclone with inv(3) and t(2;11)(p23;q23) with KMT2A break-apart (BAP) probe
set positive for rearrangement (arrows).
and t(9;22) (Fig. 1C) and eight with inv(3) and t(2;11)(p23;q23)
(Fig. 1E). No normal metaphases were observed. Consistent with
conventional chromosome results, FISH revealed GATA2-MECOM
rearrangement (Fig. 1B) and BCR-ABL1 (Fig. 1D) fusion in 86%
(cutoff: <0.6%) and 11% (cutoff: <0.6%) of interphase nuclei, re￾spectively; while a KMT2A rearrangement (Fig. 1F) was observed
in 31% (cutoff: <4%) of interphase nuclei. By quantitative BCR￾ABL1 analysis, p190 mRNA transcripts were estimated to repre￾sent 15% of total ABL1 [%BCR/ABL1:ABL1]. NGS panel testing showed
persistence of the GATA2 (44%) and SF3B1 (46%) mutations ob￾served in the diagnostic sample as well as previously undetected
pathogenic mutations in WT1 (c.938C>A; p.Ser313∗ [7%]) and in
KRAS (NM_033360.3, c.35G>A, p.Gly12Asp [9%]).
To further characterize the KMT2A rearrangement, MPseq was
performed and revealed t(2;11)(p23.3;q23.3) with breakpoints
located within KMT2A (intron 19, NM_005933) and ASXL2 (intron
4, NM_018263) (Fig 2A), resulting in an in-frame KMT2A-ASXL2
gene fusion (Fig. 2B). In addition, MPseq confirmed inv(3) and
t(9;22) as detected by conventional chromosome and FISH stud￾ies (results not shown). Stengel et al. recently reported a male
patient (case 17a) with t-AML who was found to have a complex
karyotype [46,XY,der(2)t(2;21)(p11;q22),der(11)t(2;11)(p24;q23),
,3’MLL+)] [8]. A targeted RNA sequencing fusion panel identified
two alternatively spliced transcripts supporting two in-frame
fusions between exons 9 and 10 of KMT2A (NM_005933) and exon
2 of ASXL2 (NM_018263) (Fig. 2B).
Chromosomal rearrangements involving KMT2A gene are recur￾rent abnormalities in acute leukemias and most are considered a
poor prognostic factor [2]. Most rearrangements involving KMT2A
Fig. 2. Characterization of KMT2A-ASXL2 fusion by MPseq. (A) Junction plot demon￾strating the t(2;11)(p23.3;q23.3) rearrangement with breakpoints located within
KMT2A (intron 19, NM_005933) and ASXL2 (intron 4, NM_018263) (Fig 2A), result￾ing in an in-frame KMT2A-ASXL2 gene fusion. MPseq results were visualized using
Ingenium Software. (B) Schematic of the KMT2A-ASXL2 fusion oncoprotein show￾ing breakpoint locations. Conserved protein domains (predicted by Pfam, https:
//pfam.xfam.org/) are color coded and shown in the accompanying key. The MPseq
split read sequence supporting the novel KMT2A-ASXL2 fusion is also shown. Pro￾tein diagrams were generated using ProteinPaint (https://proteinpaint.stjude.org/).
(C) Schematic showing the clonal architecture observed in this case at diagnosis
and in response to subsequent treatment.
result from balanced translocations and generate in-frame gain￾of-function fusion oncoproteins [12]. The other KMT2A wild-type
allele, with its normal methyltransferase activity, is also essential
for leukemogenesis in combination with the chimeric fusion
protein. To date, more than 135 different rearrangements involving
KMT2A have been identified, suggesting heterogeneity in function
and contribution to disease pathogenesis [13]. The most common
KMT2A rearrangement partners involve genes in the ENL-associated
protein (EAP) complex and account for approximately 70% of
KMT2A-rearranged acute myeloid leukemias [12]. As EAP complex
components interact with transcriptional cofactors such as PAF1C,
DOT1L, P-TEFb-BRD4 and CBX8-KAT5 complexes, it is thought that
KMT2A chimeric fusions function by enhancing expression of genes
Please cite this article as: P.R. Blackburn, L. Huang and A. Dalovisio et al., Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-
MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion, Cancer Genetics, https://doi.org/10.
4 P.R. Blackburn, L. Huang and A. Dalovisio et al. / Cancer Genetics xxx (xxxx) xxx
JID: CGEN [m5G;January 2, 2020;10:1]
important in leukemogenesis via regulation of transcriptional elon￾gation [12]. Additionally, KMT2A chimeric fusion oncoproteins are
able to induce leukemic transformation within the hematopoietic
stem cell niche and confer stem cell-like properties including
self-renewal and high expression of anti-apoptotic genes [12].
ASXL2 is a member of the additional sex comb-like family (in￾cludes ASXL1, 2 and 3) that function as putative polycomb group
proteins and share a conserved domain architecture consisting
of N-terminal ASXN and ASX homology (ASXH) domains, central
ASXM1 and ASXM2 domains, and a C-terminal plant homedomain
(PHD) [14]. Essential for normal hematopoiesis, ASXL2 has both
overlapping and distinct functions compared to ASXL1 and has
been shown to act as a haploinsufficient tumor suppressor [7,15].
ASXL1 has been experimentally shown to recruit the polycomb re￾pressive complex 2, which results in mono-, di-, and trimethyla￾tion of histone H3 lysine 27 [15]. ChIP-seq experiments in mice
revealed that loss of Asxl2 leads to changes in the levels of histone
enhancer marks, including H3K27ac, H3K4me1, and H3K4me2, and
leads to increased chromatin accessibility near genes important for
myeloid and hematopoietic cell development, including direct tar￾gets of RUNX1 and RUNX1-RUNX1T1 [15]. ASXL2 loss-of-function
mutations are largely restricted to patients with t(8;21)/RUNX1-
RUNX1T1 AML (10% of AML cases overall), and are seen in ap￾proximately ~23% of adult and pediatric populations [6]. ASXL1
and ASXL2 loss-of-function mutations are mutually exclusive in
t(8;21)/RUNX1-RUNX1T1 AML, suggesting a common mechanism
and perhaps synthetic lethal effects in promoting leukemogenesis
While the functional significance of the KMT2A-ASXL2 fusion
is unknown, we hypothesize that it potentially drives leukemo￾genesis/clonal evolution by enhancing gene expression via tran￾scriptional elongation (KMT2A) and increased chromatin acces￾sibility (ASXL2—assuming the fusion has loss-of-function effects)
near enhancers at disease relevant loci. Of note, ASXL1 loss-of￾function mutations have also been observed as secondary so￾matic events in patients with congenital GATA2-related immun￾odeficiency and susceptibility to hematological malignancies [16].
Interestingly, a c.961C>T; p.Leu321Phe GATA2 mutation was ob￾served in the ancestral inv(3) clone identified in our patient at
~50% MAF, suggesting that the KMT2A-ASXL2 fusion may function
as a collaborating secondary event in the evolution of the t(2;11)
subclone. Additionally, dysregulated expression of the MECOM gene
caused by translocation or inversion between 3q21 (which con￾tains a distant GATA2 hematopoietic enhancer) and 3q26 is a
hallmark of inv(3)/t(3;3)/GATA2-MECOM AML [17]. Overall, ASXL1/2
mutation status does not appear to impact clinical outcome in
t(8;21)/RUNX1-RUNX1T1 positive AML and it is likely that inv(3) is
the more clinically significant abnormality indicating a poor prog￾nosis in this patient [6,18–20].
Regarding the inv(3)/t(9;22) subclone, only four cases of AML
including our own have been reported with concomitant inv(3)
and t(9;22) at diagnosis [21]. Han et al. reported a case with p190
BCR-ABL1 fusion in the context of inv(3) and monosomy 7 at di￾agnosis, similar to the p190 fusion observed in our patient [21].
Mozziconacci et al. reported a similar case in which t(9;22) pre￾sented as a secondary abnormality in inv(3) acute megakaryoblas￾tic leukemia (AMKL) at diagnosis [22]. Lastly, Shi et al. described
case of chronic phase CML, where the BCR-ABL1 rearrangement
also resulted from the evolution of an ancestral clone with inv(3)
at diagnosis [23]. The BCR-ABL1 molecular transcript was not de￾termined in either of these cases, however both the p190 and p210
forms have been reported in BCR-ABL1 positive AML with an equal
distribution [1]. Acquisition of inv(3) in the accelerated phase of
CML has been well documented and these patients typically do
not respond to TKI treatment [2,3,24]. Neuendorff et al. reviewed
the clinical course of relapsed BCR-ABL1 positive AML cases treated
with TKI and found seven patients; one patient achieved a com￾plete cytogenetic response but subsequently died, two patients had
a transient response, three patients showed a complete response
of the BCR-ABL1 positive clone despite active disease, and two pa￾tients had no response to treatment [1]. A patient described in
this report also had a partial response with disappearance of the
BCR-ABL1 positive clone in response to treatment with single agent
TKI (imatinib). Consistent with previous reports, the BCR-ABL1 re￾arrangement did not appear to be the key driver of the disease
in this patient, but likely provides a proliferative advantage (func￾tions as a class-I mutation) within this subclone and reemerged
later during relapse (Fig. 2C) [1].
The unusual combination of abnormalities in this patient is
overall suggestive of a poor prognosis and to date he has only
achieved transient morphologic remission while on a combination
of FLAG with TKI. The most recent relapse is notable for the emer￾gence of KMT2A-ASXL2 fusion that is likely another distinct sec￾ondary collaborating event in the evolution of the inv(3) ances￾tral clone in addition to BCR-ABL1 fusion noted at diagnosis. The
KMT2A-ASXL2 fusion has only been reported in one other case of t￾AML, and to our knowledge no KMT2A-ASXL1 rearrangements have
been so far described, suggesting that this may be a rare entity in
the pathogenesis of some hematologic neoplasms.
Declaration of Competing Interest
RPK, LBB and JFP: no financial disclosures. GV: Algorithms de￾scribed in this manuscript for mate-pair sequencing are licensed
to WholeGenome LLC owned by GV.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.cancergen.2019.12.005.
[1] Neuendorff NR, Burmeister T, Dörken B, Westermann J. BCR-ABL-positive acute
myeloid leukemia: a new entity? Analysis of clinical and molecular features.
Ann Hematol 2016;95(8):1211–21.
[2] Arber DA, Bunning RD, Le Beau MM, et al. Acute myeloid leukemia with recur￾rent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., editors.
WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon,
France: IARC; 2017. p. 130–49.
[3] Wang W, Cortes JE, Lin P, et al. Clinical and prognostic significance of 3q26.2
and other chromosome 3 abnormalities in CML in the era of tyrosine kinase
inhibitors. Blood 2015;126(14):1699–706.
[4] Kelemen K, Galani K, Conley CR, Greipp PT. Secondary Philadelphia chromo￾some and erythrophagocytosis in a relapsed acute myeloid leukemia after
hematopoietic cell transplantation. Cancer Genet 2014;207(6):268–71.
[5] Bacher U, Haferlach T, Alpermann T, et al. Subclones with the
t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate
with distinct genetic alterations. Br J Haematol 2011;152(6):713–20.
[6] Micol J-B, Duployez N, Boissel N, et al. Frequent ASXL2 mutations in
acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal
translocations. Blood 2014;124(9):1445–9.
[7] Micol J-B, Pastore A, Inoue D, et al. ASXL2 is essential for haematopoiesis
and acts as a haploinsufficient tumour suppressor in leukemia. Nat Commun
[8] Stengel A, Nadarajah N, Haferlach T, et al. Detection of recurrent and of
novel fusion transcripts in myeloid malignancies by targeted RNA sequencing.
Leukemia 2018;32(5):1229–38.
[9] Shearer BM, Sukov WR, Flynn HC, Knudson RA, Ketterling RP. Development of
a dual-color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associ￾ated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute
myeloid leukemia. Am J Hematol 2010;85(8):569–74.
[10] Drucker TM, Johnson SH, Murphy SJ, Cradic KW, Therneau TM, Vasmatzis G.
BIMA V3: an aligner customized for mate pair library sequencing. Bioinformat￾ics 2014;30(11):1627–9.
[11] Johnson SH, Smadbeck JB, Smoley SA, et al. SVAtools for junction detection of
genome-wide chromosomal rearrangements by mate-pair sequencing (MPseq).
Cancer Genet 2018;221:1–18.
Please cite this article as: P.R. Blackburn, L. Huang and A. Dalovisio et al., Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-
MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion, Cancer Genetics, https://doi.org/10.
P.R. Blackburn, L. Huang and A. Dalovisio et al. / Cancer Genetics xxx (xxxx) xxx 5
JID: CGEN [m5G;January 2, 2020;10:1]
[12] Rao RC, Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltrans￾ferases. Nat Rev Cancer 2015;15(6):334–46.
[13] Meyer C, Burmeister T, Gröger D, et al. The MLL recombinome of acute
leukemias in 2017. Leukemia 2018;32(2):273–84.
[14] Micol J-B, Abdel-Wahab O. The role of additional sex combs-like proteins in
cancer. Cold Spring Harb Perspect Med 2016;6(10).
[15] Li J, He F, Zhang P, et al. Loss of Asxl2 leads to myeloid malignancies in mice.
Nat Commun 2017;8(1):15456.
[16] Micol J-B, Abdel-Wahab O. Collaborating constitutive and somatic genetic
events in myeloid malignancies: ASXL1 mutations in patients with germline
GATA2 mutations. Haematologica 2014;99(2):201–3.
[17] Yamazaki H, Suzuki M, Otsuki A, et al. A remote GATA2 hematopoietic en￾hancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression.
Cancer Cell 2014;25(4):415–27.
[18] Yamato G, Shiba N, Yoshida K, et al. ASXL2 mutations are frequently found in
pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a
better prognosis. Genes Chromosom Cancer 2017;56(5):382–93.
[19] Jahn N, Agrawal M, Bullinger L, et al. Incidence and prognostic im￾pact of ASXL2 mutations in adult acute myeloid leukemia patients with
t(8;21)(q22;q22): a study of the German-Austrian AML Study Group. Leukemia
[20] Rogers HJ, Vardiman JW, Anastasi J, et al. Complex or monosomal
karyotype and not blast percentage is associated with poor survival
in acute myeloid leukemia and myelodysplastic syndrome patients with
inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study.
Haematologica 2014;99(5):821–9.
[21] Han J-Y, Theil KS. The Philadelphia chromosome as a secondary abnormality
in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190
BCRABL mRNA by real-time quantitative polymerase chain reaction. Cancer
Genet Cytogenet 2006;165(1):70–4.
[22] Mozziconacci MJ, Sainty D, Gabert J, et al. The Philadelphia chromosome as a
secondary abnormality in two cases of acute myeloid leukemia. Br J Haematol
[23] Shi G, Weh HJ, Dührsen U, Zeller W, Hossfeld DK. Chromosomal abnor￾mality inv(3)(q21q26) associated with multilineage hematopoietic progeni￾tor cells in hematopoietic malignancies. Cancer Genet Cytogenet 1997;96(1):
[24] Theil KS, Cotta CV. The prognostic significance of an inv(3)(q21q26.2) in addi￾tion to a t(9;22)(q34;q11.2) in Fludarabine patients treated with tyrosine kinase inhibitors.
Cancer Genetics 2014;207(5):171–6.
Please cite this article as: P.R. Blackburn, L. Huang and A. Dalovisio et al., Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-
MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion, Cancer Genetics, https://doi.org/10.