Home > Bone marrow neoplastic > AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

Bone marrow neoplastic

Bone marrow - neoplastic myeloid

AML with recurrent genetic abnormalities

AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

Authors: Oluwatobi "Tobi" Odetola, M.D., Kamran M. Mirza, M.D., Ph.D.

Editorial Board Member: Patricia Tsang, M.D., M.B.A.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Last author update: 21 December 2020

Last staff update: 9 February 2022

Copyright: 2020-2023, PathologyOutlines.com, Inc.

PubMed Search: inv3 q21;q26.2 OR t3;3 q21;q26.2

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Table of Contents

Cite this page: Odetola O, Mirza KM. AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLinv3q21q26.html. Accessed May 30th, 2023.

Definition / general

A distinct acute myeloid leukemia (AML) subcategory recognized by presence of the pathognomonic cytogenetic abnormality inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] (Blood 2016;127:2391)
Recognized as a separate entity in the acute myeloid leukemia (AML) category of the 2008 WHO classification and updated in the 2016 revision (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th Edition, 2008, Blood 2016;127:2391)
May present as de novo disease or evolve from preexisting myelodysplastic syndrome (Cancer Genet 2019;230:28)
Diagnosis requires ≥ 20% blasts (in peripheral blood or bone marrow) and is often clinically characterized by anemia, normal to elevated platelet counts and bone marrow hyperplasia with multilineage dysplasia of nonblast cells, particularly dysmegakaryocytopoiesis (Cancer Genet 2019;230:28)
Aggressive form of AML with very poor prognosis and poor response to conventional induction chemotherapy (Cancer Genet 2019;230:28)

Essential features

Aggressive form of AML with very poor prognosis and poor response to conventional induction chemotherapy (Cancer Genet 2019;230:28)
Diagnosed by presence of the pathognomonic cytogenetic abnormality inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] (Blood 2016;127:2391)
End result is juxtaposition of the distal GATA2 enhancer with the MECOM (EVI1) proto-oncogene (Blood 2016;127:2391)
May present as de novo disease or evolve from preexisting myelodysplastic syndrome (Cancer Genet 2019;230:28)

Terminology

AML with inv(3)
Acute myeloid leukemia with GATA2, MECOM
AML with RPN1 / EVI1
3q21q26 syndrome (Hematology 2015;20:435)
AML with RPN1-MECOM

ICD coding

ICD-0: 9869/3 - acute myeloid leukemia with inv(3)(q21;q26.2) or t(13.3)(q21;q26.2); RPN1-EVI1 (NIH: Acute Myeloid Leukemia with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM [Accessed 16 July 2020])
ICD-10: C92.0 - acute myeloblastic leukemia

Epidemiology

More frequent in people younger than 60 years (median age of 50 years) (Hematology 2015;20:435)
Slight male predominance (54%) (Hematology 2015;20:435)
1 - 2% of all forms of AML (Cancer Genet 2019;230:28)

Sites

Bone marrow
Peripheral blood

Pathophysiology

See Etiology

Etiology

Recurrent cytogenetic abnormality, inv(3)(q21q26.2) / t(3;3)(q21;q26.2), causes a juxtaposition of the distal GATA2 enhancer with MECOM (EVI1) (Blood 2016;127:2391)
These rearrangements (not to be thought of as a fusion) result in the proto-oncogene MECOM (EVI1) at 3q26 (Blood 2016;127:2391, Cancer Cell 2014;25:415)
Simultaneous GATA2 haploinsufficiency also results (Blood 2016;127:2391)
Core mRNA splicing factor SF3B1 and RAS / RTK signaling pathways have been found to be important in the pathogenesis of this AML subtype (Blood 2019;134:917, Blood 2015;125:133)
Secondary karyotypic abnormalities, including monosomy 7 (most common), complex karyotype and 5q deletion, are commonly present (Cancer Genet 2019;230:28, Hematology 2015;20:435, J Clin Oncol 2010;28:3890)

Clinical features

Presence of at least 20% blasts in peripheral blood or bone marrow
Often presents with anemia
Elevated white blood cell count (sometimes low)
Normal or elevated platelet count
Association with central diabetes insipidus (Hematology 2015;20:435)
Elevated LDH

Diagnosis

Requires enumeration of 20% blasts on peripheral blood smear or marrow aspirate differential count(s)
Flow cytometry or immunohistochemical stains may assist in blast phenotyping
Juxtaposition of GATA2 and MECOM, inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] can be detected by classic cytogenetics, FISH and other molecular / genetic studies including chromosome microarray, next generation sequencing, RT-PCR, etc.

Laboratory

CBC with anemia
Leukocytosis (sometimes leukopenia) with 20% blasts
Normal or elevated platelet count
Elevated LDH
Flow cytometry analysis reveals increased dim CD45 events (blasts)

Prognostic factors

inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] finding in AML itself represents a very poor prognosis and predicts poor response to conventional induction chemotherapy (Hematology 2015;20:435, J Clin Oncol 2010;28:3890)
Age greater than 60 years at diagnosis indicates poor prognosis (Hematology 2015;20:435)
High WBC count at diagnosis confers poor prognosis (Hematology 2015;20:435)
Presence of monosomy 7 has been reported to be an indicator of poor prognosis (J Clin Oncol 2010;28:3890)
- However, this has not proven to be a consistent finding in other studies (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)

Case reports

Young woman with AML and concurrent central diabetes insipidus in the presence of inversion(3)(q21q26) (Blood Cells Mol Dis 2019;76:45)
25 year old woman with germline GATA2 mutation and acquired NRAS Q61K mutation who presents with rapid progression to AML (Leuk Res Rep 2019;12:100176)
77 year old man with a variant of AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) (MECOM) rearrangement (Mol Cytogenet 2015;8:68)
Case series of AML with double inv(3)(q21q26.2) (J Clin Oncol 2010;28:3890)

Treatment

This subtype of AML is well known to show poor response to standard induction chemotherapy (such as the 7 + 3 regimen consisting of cytarabine and an anthracycline), with remission rates of only 10 - 30% and overall survival of < 10% at 8 - 10 months (Hematology 2015;20:435, J Clin Oncol 2010;28:3890, Clin Lymphoma Myeloma Leuk 2020;20:24)
Combination of lenalidomide and a hypomethylating agent (azacitidine of decitabine), has shown promise with improved overall response rates, particularly when used as first line therapy (J Clin Oncol 2010;28:3890)
Stem cell transplantation does not appear to conclusively improve overall survival in this subtype of AML (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)

Microscopic (histologic) description

20% blasts in the peripheral blood with or without dysplastic features
Hypercellular (often) bone marrow with > 20% blasts (Int J Lab Hematol 2019;41:380)
Multilineage dysplasia with variable bone marrow fibrosis (usually little or no reticulin fibrosis) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Prominence of mono or bilobed megakaryocytes in the bone marrow (Hematology 2015;20:435)
Micromegakaryocytes have been described (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Binuclear granulocytes (pseudo-Pelger-Hüet neutrophils) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Morphological features often resemble AML without maturation and acute myelomonocytic leukemia (Blood 2016;127:2391)
- However, a study of Asian patients found acute monoblastic and monocytic leukemia in nearly half of the patients (Int J Lab Hematol 2019;41:380)

Microscopic (histologic) images

Contributed by Alexa J. Siddon, M.D.

Hypercellular marrow with increased blasts

Cytology images

Contributed by Alexa J. Siddon, M.D.

Aspirate with hypolobated megakaryocyte

Aspirate with blasts

Peripheral smear description

Anemia with erythroid dysplasia
Leukocytosis or leukopenia
Binuclear granulocytes (pseudo-Pelger-Hüet neutrophils) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Thrombocytosis or thrombocytopenia

Positive stains

See Flow cytometry description

Negative stains

See Flow cytometry description

Flow cytometry description

No characteristic immunophenotypic profile
Myeloperoxidase (33 - 42.3% of cases) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Expression of panmyeloid and immature markers: CD34, CD13, CD33, CD117, CD38 and HLA-DR (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
Aberrant expression of CD7, a lymphoid marker (42.3 - 60%) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
CD56 (20%) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
CD41, a megakaryocytic marker in 15.8% of patients (Hematology 2015;20:435)
- Less frequent expression in patients of Asian origin (Int J Lab Hematol 2019;41:380)

Molecular / cytogenetics description

inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)]
Increased expression of EVI1 (MECOM)
Relative haploinsufficiency of GATA2
Associated monosomy 7, complex karyotype and 5q deletion
Gene mutations identified include those of NRAS, GATA2, SF3B1, FLT3-ITD, KIT D816, PTPN11, CBL, KRAS and BCR-ABL1 and CEBPA (Blood 2015;125:133, Int J Lab Hematol 2019;41:380)

Molecular / cytogenetics images

Images hosted on other servers:

Double inv(3)(q21q26) and monosomy 7

FISH with EVI1 breakapart probe

Sample pathology report

Right posterior iliac crest, core biopsy, aspirate smear, touch imprint and clot particle:
- Acute myeloid leukemia with inv(3)(q21.3;q26.2); GATA2, MECOM (see comment)
- Comment: The bone core biopsy demonstrates an increase in blasts and prominent dysmegakaryocytopoiesis. The presence of inv(3)(q21.3;q26.2) confirms above diagnosis.

Differential diagnosis

Other AML with recurrent cytogenetic abnormalities:
- Presence of other subtype defining cytogenetic abnormalities different from inv(3) / t(3;3)
MDS with inv(3):
- Blast count < 20%

Board review style question #1

Which of the following is true about AML with inv(3) / t(3;3)?

CD41 positivity on immunophenotypic studies is a key part of the diagnostic criteria
Deletion of chromosome 5q is the most frequently associated cytogenetic abnormality
Expression of CD7 is not consistent with the entity
Expression of MECOM (EVI1) is commonly upregulated
GATA2 fusion with MECOM (EVI1) is the characteristic molecular feature

Board review style answer #1

D. Expression of MECOM (EVI1) is commonly upregulated

Comment Here

Reference: AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2)

Board review style question #2

Which of the following is true about AML with inv(3) / t(3;3)?

Anemia and thrombocytopenia are hallmark findings on the peripheral smear
Bone marrow is often hypocellular with extensive fibrosis
Erythroid dysplasia is uncommon unlike in other subtypes of AML
Finding of pseudo-Pelger-Hüet neutrophils suggest an alternative diagnosis
Increased megakaryocytic dysplasia is commonly observed on bone marrow aspiration / biopsy

Board review style answer #2

E. Increased megakaryocytic dysplasia is commonly observed on bone marrow aspiration / biopsy

Comment Here

Reference: AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2)

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