Bone marrow neoplastic

Bone marrow - neoplastic myeloid

AML with other rare recurrent translocations

AML with RUNX1T3(CBFA2T3)::GLIS2



Last author update: 8 May 2024
Last staff update: 8 May 2024

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PubMed Search: AML with RUNX1T3(CBFA2T3)::GLIS2

Ivan De La Riva-Morales, M.D.
Barina Aqil, M.D.
Page views in 2024 to date: 59
Cite 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 May 19th, 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
  • ICD-O: 9861/3 - acute myeloid leukemia, NOS
  • ICD-10: C92.0 - acute myeloid leukemia
  • ICD-11: 2A60.0 - acute myeloid leukemia with recurrent genetic abnormalities
Epidemiology
Sites
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
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
Prognostic factors
Case reports
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

Atypical mononuclear cells

Blast morphology

Blast morphology

Increased blasts

Increased blasts

Blasts

Blasts

Peripheral smear description
Peripheral smear images

Contributed by Barina Aqil, M.D.
Circulating blasts

Circulating blasts

Positive stains
Flow cytometry description
Molecular / cytogenetics description
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
Board review style question #1

What characteristic phenotype panel is seen in acute myeloid leukemia with CBFA2T3::GLIS2?

  1. CD34, CD56, CD38, HLA-DR
  2. CD34, CD117, CD13, CD33
  3. CD34, CD117, CD41, CD61
  4. 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.

Comment Here

Reference: AML with RUNX1T3(CBFA2T3)::GLIS2
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