Bone marrow neoplastic
Bone marrow - neoplastic myeloid
AML with other rare recurrent translocations
AML with RUNX1T3(CBFA2T3)::GLIS2
Editorial Board Member: Alexa J. Siddon, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Last author update: 8 May 2024
Last staff update: 8 May 2024
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PubMed Search: AML with RUNX1T3(CBFA2T3)::GLIS2
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1Cite this page: De La Riva-Morales I, Aqil B. AML with RUNX1T3(CBFA2T3)::GLIS2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLRUNX1T3.html. Accessed December 2nd, 2024.
Definition / general
- Acute myeloid leukemia (AML) with CBFA2T3(RUNX1T3)::GLIS2 is a rare subtype of pediatric AML
Essential features
- Pediatric acute myeloid leukemia with dismal prognosis
- CBFA2T3::GLIS2 is the most common alteration seen in non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL)
- Often expressing the unique RAM phenotype by flow cytometry with bright CD56 and lack of HLA-DR and CD38 expression
ICD coding
Epidemiology
- Exclusively seen in pediatric population, especially < 5 years of age with predominance in infants (Cancer Cell 2012;22:683, Blood 2013;121:3469, J Hematol Oncol 2017;10:26)
- Comprises almost 30% of pediatric non-DS AMKL (Nat Genet 2017;49:451, Cancer Cell 2012;22:683)
Sites
- Peripheral blood, bone marrow, lymph node, 1 reported case with a paraspinal mass (Cancer Cell 2012;22:683, EJHaem 2023;4:765)
Pathophysiology
- Cryptic inversion on chromosome 16 [inv(16)(p13.3q24.3)] results in the joining of CBFA2T3, a member of the ETO family of nuclear corepressors, to GLIS2, a member of the GLI family of transcription factors (Cancer Cell 2012;22:683)
- CBFA2T3 and GLIS2 genes are both localized, in inverted orientation, on each arm of chromosome 16 close to the telomeres, in 16q24.3 and 16p13.3, respectively (Cancer Cell 2012;22:683)
- CBFA2T3::GLIS2 fusion transcript leads to upregulation of BMP2 (bone morphogenetic proteins) and GATA3, a downstream target of Hedgehog signaling as well as JAK-STAT pathway (J Exp Med 2012;209:2017, Development 2004;131:1165, Cancer Cell 2012;22:683)
Etiology
- Not known
Clinical features
- Median age of diagnosis is 1.26 - 1.5 years of age (Leukemia 2016;30:2077, Blood 2016;127:3424)
- Case reports have described leukocytosis and extensive lymphadenopathy (Leuk Res Rep 2021;17:100287, EJHaem 2023;4:765)
- Extramedullary involvement is more frequent in patients expressing the CBFA2T3::GLIS2 chimeric gene (25%) compared to the frequency reported for pediatric AML in general (Blood 2013;121:3469, Blood 2013;122:170)
- It is seen in non-Down syndrome patients
Diagnosis
- Diagnostic criteria per World Health Organization (WHO) Classification of Tumors, 2022 requires ≥ 20% myeloid blasts in the peripheral blood or bone marrow and detection of CBFA2T3::GLIS2 (Leukemia 2022;36:1703)
- International Consensus Classification (ICC), 2022 requires ≥ 10% myeloid blasts in the bone marrow or peripheral blood (Blood 2022;140:1200)
- Must exclude the diagnostic criteria for AML with other defining genetic abnormalities, AML MR (AML myelodysplasia related), AML pCT (postcytotoxic therapy) or MPAL (mixed phenotype acute leukemia)
- This entity is recognized by the WHO 5th edition under AML with other defined genetic alterations but is not a specific entity within the ICC
Laboratory
- Leukocytosis with increased blasts (≥ 10% per ICC; ≥ 20% per WHO 5th edition) (Leukemia 2022;36:1703, Blood 2022;140:1200)
- No differences are reported with reference to white blood cell count (WBC), bone marrow blast percentage, platelet count or hemoglobin levels as compared to other AML subtypes (Leukemia 2016;30:2077)
- CBFA2T3::GLIS2 positive AML patients tend to have a higher percentage of bone marrow blasts at diagnosis compared to fusion negative patients (Blood 2016;127:3424, Genes Chromosomes Cancer 2017;56:394)
Prognostic factors
- CBFA2T3::GLIS2 AML has dismal outcome (Nat Genet 2017;49:451)
- 5 year overall survival is ~30% (Cancer Cell 2012;22:683)
Case reports
- 5 month old girl with leukocytosis, eosinophilia and paraspinal mass (EJHaem 2023;4:765)
- 12 month old girl presented with bruising and found to have marked leukocytosis and skin nodules (Cold Spring Harb Mol Case Stud 2022;8:a006220)
- 1 year old girl presented with fever, cytopenias and hepatosplenomegaly (Leuk Lymphoma 2023;64:2042)
- 2 year old monozygotic twins presented simultaneously with RAM AML (Pediatr Transplant 2018;22:e13291)
- 5 year old boy with extensive mesenteric and retroperitoneal lymphadenopathy (Leuk Res Rep 2021;17:100287)
Treatment
- Patients may benefit from intensive chemotherapy followed by allogeneic stem cell transplant as postremission intensification strategy (Pediatr Transplant 2018;22:e13291)
- Overexpression of the folate receptor 1 (FOLR1) gene has shown great result with targeted therapy (J Clin Invest 2022;132:e157101)
- Navitoclax or DT2216 treatment in combination with low dose cytarabine has been found effective in murine models (Blood Adv 2024;8:112)
Microscopic (histologic) description
- No specific morphological features have been found associated with this fusion gene (Blood 2013;121:3469)
- In AMKL CBFA2T3::GLIS2 positive patients, megakaryoblasts are reported as the predominant component of the blast population in bone marrow or peripheral blood (Br J Haematol 2019;184:337)
- Megakaryoblasts are large cells with abundant cytoplasm and prominent nucleoli; they often display cytoplasmic blebs or pseudopods
- In one of the pediatric studies, 50% (N = 10) of the fusion positive patients had a non-FAB M7 subtype, others were distributed as follows: M5 (15%), M0 (15%), M1 (10%), M2 (5%), M4 (5%) (Blood 2013;121:3469)
Microscopic (histologic) images
Contributed by Barina Aqil, M.D.
Atypical mononuclear cells
Blast morphology
Increased blasts
Blasts
Peripheral smear description
- Circulating blasts as previously described
Peripheral smear images
Contributed by Barina Aqil, M.D.
Circulating blasts
Negative stains
Flow cytometry description
- RAM phenotype was named after the patient's initials in original study (Leukemia 2016;30:2077)
- Bright CD56 expression (at minimum 2 log10 units greater than normal myeloid progenitors)
- Dim to negative expression of CD45, CD38 and lack of HLA-DR
- Reported cases have shown aberrant expression of T and B cell markers, such as cytoplasmic CD3 and CD19 (EJHaem 2023;4:765, Leuk Lymphoma 2023;64:462)
Molecular / cytogenetics description
- Concomitant cytogenetic abnormalities are rare in patients with CBFA2T3::GLIS2 (Br J Haematol 2019;184:337)
- In cases of abnormal karyotype, complex aberrations, trisomy 21 and hyperdiploidy have been noted (Cancer Cell 2012;22:683, Nat Genet 2017;49:451, Genes Chromosomes Cancer 2017;56:394)
- Somatic mutations are significantly lower than other subgroups of AMKL (Cancer Cell 2012;22:683, Nat Genet 2017;49:451)
- GATA1, KIT and FLT3 mutations are less frequently noted in CBFA2T3::GLIS2 positive than in negative cases (Br J Haematol 2019;184:337)
- RAS and JAK-STAT pathway mutations are reported more often (Cancer Cell 2012;22:683, Nat Genet 2017;49:451)
Sample pathology report
- Peripheral blood, bone marrow aspirate and left posterior iliac crest bone marrow core biopsy:
- Acute myeloid leukemia with CBFA2T3::GLIS2 extensively involving a hypercellular (virtually 100%) bone marrow (see comment)
- Flow cytometric immunophenotyping of the bone marrow aspirate reveals a blast population (~90% of cellular events) with a dim to negative CD45 expression that is positive for CD34, bright positive for CD56 and negative for CD38 and HLA-DR.
- Comment: The overall morphologic, immunophenotypic and genetic findings are consistent with a diagnosis of acute myeloid leukemia with CBFA2T3::GLIS2.
- Peripheral blood smear: The peripheral blood smear shows predominantly circulating blasts (90%) that are large in size with abundant cytoplasm and frequent prominent nucleoli with occasional cytoplasmic blebs. Normocytic normochromic anemia is present with rare nucleated red blood cells. There is absolute neutropenia and lymphopenia. Thrombocytopenia with rare large platelets.
- Bone marrow aspirate smear: The majority of the cells present are blasts with similar morphology as seen in the peripheral blood. Background hematopoiesis is markedly decreased. Rare megakaryocytes are seen.
- Bone marrow core biopsy (decalcified) / particle clot: The bone marrow is markedly hypercellular for age (~100%) and is composed almost entirely of blasts. Very rare myeloid and erythroid precursors are present. The particle clot shows multiple bone marrow particles composed predominantly of blasts.
Differential diagnosis
- AML with minimal differentiation (M0):
- AML with RUNX1::RUNX1T1:
- Mixed phenotype acute leukemia, T / myeloid:
- Early T precursor lymphoblastic leukemia / lymphoma:
- Acute megakaryoblastic leukemia (M7):
- Myeloid proliferations associated with Down syndrome:
- Transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML-DS) are 2 clonal conditions seen in patients with trisomy 21
- TAM presents usually in the first 7 days of life while ML-DS onset is 1.6 years (Br J Haematol 2018;182:200, J Clin Oncol 2014;32:3021, Blood 2017;129:3304)
- Blast morphology ranges from undifferentiated myeloid blasts to megakaryoblasts
- Blasts express CD117 with variable expression of CD34, CD36, CD41 / 42b or CD235a (glycophorin A)
- Exon 2/3 somatic GATA1 mutations are seen (Blood 2011;118:2222, Nat Genet 2013;45:1293, Cancer Cell 2019;36:123)
- In ML-DS additional mutations are also identified, such as cohesin complex, EZH2, KANSL1 or JAK3 (Nat Genet 2013;45:1293, Cancer Cell 2019;36:123)
Board review style question #1
What characteristic phenotype panel is seen in acute myeloid leukemia with CBFA2T3::GLIS2?
- CD34, CD56, CD38, HLA-DR
- CD34, CD117, CD13, CD33
- CD34, CD117, CD41, CD61
- CD34, TdT, CD19, CD79a
Board review style answer #1
A. CD34, CD56, CD38, HLA-DR. The blasts have characteristic phenotype CD56+, CD38 and CD45 (negative to dim) and HLA-DR-. Answer B is incorrect because it is the antibody panel for acute myeloid leukemia. Answer C is incorrect because it is the panel for acute megakaryoblastic leukemia. Answer D is incorrect because it is the panel for B lymphoblastic leukemia. This phenotype is not specific to this AML subtype but is characteristically seen.
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Reference: AML with RUNX1T3(CBFA2T3)::GLIS2
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Reference: AML with RUNX1T3(CBFA2T3)::GLIS2
