Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Recurrent genetic abnormalities
AML with mutated RUNX1


Minor changes: 11 January 2021

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: RUNX1[TI] AML[TI]

Oluwatobi
Kamran M. Mirza, M.D., Ph.D.
Page views in 2020: 189
Page views in 2021 to date: 220
Cite this page: Odetola O, Mirza KM. AML with mutated RUNX1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLmutatedRUNX1.html. Accessed April 19th, 2021.
Definition / general
  • Provisional entity in the 2016 WHO classification
  • De novo acute leukemia diagnosed with ≥ 20% blasts in blood or bone marrow
  • All morphological subtypes of AML, NOS may harbor RUNX1 mutation, with the highest frequency being AML with minimal differentiation
  • Diagnosis of AML with mutated RUNX1 excludes cases that fulfill criteria for other specific AML with recurrent genetic abnormalities, therapy related myeloid neoplasms or AML with myelodysplasia related changes (Blood 2016;128:462, Leukemia 2016;30:2282)
  • Unfavorable prognostic implication, with mutated RUNX1 being associated with inferior survival than wildtype (Leukemia 2016;30:2282, J Clin Oncol 2012;30:3109)
Essential features
  • Provisional WHO entity describing a de novo acute myeloid leukemia
  • Cases possess monoallelic RUNX1 mutations (typically frameshift or missense)
  • Blast morphology most compatible with M0
  • Cases do not meet diagnostic criteria for other AML with genetic abnormality
  • Highest incidence in men and patients over 60 years of age
  • Associated gene mutations include those of SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%) and SF3B1 (17%) (Leukemia 2018;32:295)
  • Other coexisting gene mutations include those of FLT3-ITD, TET2, RAS, PTPN11, p53, JAK2 and EZH2 genes (Leukemia 2018;32:295)
ICD coding
Epidemiology
Sites
  • Peripheral blood
  • Bone marrow
Etiology
  • Runt related transcription factor 1 (RUNX1) is known to play a key role in hematopoiesis as a key regulator of genes involved in the differentiation of myeloid cells (Int J Mol Sci 2017;18:1618)
  • RUNX1 mutation leads to upregulation of those genes normally expressed in primitive hematopoietic cells and B cell progenitors and downregulation of promoters of myelopoiesis (J Clin Oncol 2012;30:3109)
  • Mutation of RUNX1 therefore predisposes to the development of AML with more immature / undifferentiated morphology (M0 in the French-American-British [FAB] classification) (Leukemia 2016;30:2282, Int J Mol Sci 2017;18:1618)
  • Associated gene mutations include those of SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%) and SF3B1 (17%) (Leukemia 2018;32:295)
  • Other coexisting gene mutations include those of FLT3-ITD, TET2, RAS, PTPN11, p53, JAK2 and EZH2 genes (Leukemia 2018;32:295)
Clinical features
  • Anemia
  • Leukopenia
  • Thrombocytopenia
  • Low LDH
Diagnosis
  • Bone marrow aspiration / biopsy to enumerate ≥ 20% blasts
  • Flow cytometric evaluation of peripheral blood and bone marrow aspirate to confirm blast phenotype
  • FISH, next generation sequencing (NGS) or mutational analysis to evaluate for any¬†RUNX1¬†alterations
Prognostic factors
Case reports
Treatment
  • AML with mutated RUNX1 is currently treated with standard induction chemotherapy, including regimens consisting of cytarabine and an anthracycline
  • Use of hypomethylating agent may negate the effect of RUNX1 in elderly patients (Int J Mol Sci 2017;18:1618)
  • Stem cell transplantation is a therapeutic option for suitable patients
  • Use of BET protein inhibitors in combination with agents such as venetoclax, decitabine or cytarabine, has shown promise in vitro (Leukemia 2018;32:295)
Microscopic (histologic) description
  • Majority of cases (~60%) show the M0 (FAB classification) morphology, with very immature / undifferentiated cells (Int J Mol Sci 2017;18:1618, Blood 2011;117:2348)
  • Blasts have variable size, high nucleus to cytoplasmic ratio and variably prominent nucleoli with no evidence of differentiation
  • M2 and M1 morphology are the next most common (Blood 2011;117:2348)
  • RUNX1 mutated AMLs typically demonstrate high bone marrow blast counts (Blood 2011;117:2348)
Microscopic (histologic) images

Contributed by Genevieve M. Crane, M.D., Ph.D.
Bone marrow core biopsy Bone marrow core biopsy Bone marrow core biopsy

Bone marrow core biopsy

Bone marrow clot, AML mutated RUNX1

Bone marrow clot

Bone marrow clot, CD34

Bone marrow clot, CD34

Bone marrow clot, CD117

Bone marrow clot, CD117

Cytology images

Contributed by Genevieve M. Crane, M.D., Ph.D.
Bone marrow aspirate with increased blasts

Bone marrow aspirate with increased blasts

Peripheral smear description
  • Lower hemoglobin, white blood cell and blast counts compared with wild type RUNX1
  • Thrombocytopenia
Peripheral smear images

Contributed by Genevieve M. Crane, M.D., Ph.D.
Peripheral blood smear with increased blasts

Peripheral blood smear with increased blasts

Positive stains
Negative stains
  • Stains for B and T cell differentiation are negative
Molecular / cytogenetics description
  • Mutation of RUNX1 (located on chromosome 21q22.12) is disease defining (Blood 2016;128:462)
    • Most RUNX1 mutations are monoallelic, within the runt homology domain (RHO) and the transactivation domain (TAD)
    • RUNX1 mutations are typically frameshift or missense
  • Known associated gene mutations include those of SRSF2, ASXL1, DNMT3A, IDH2, SF3B1, FLT3-ITD, TET2, RAS, PTPN11, p53, JAK2 and EZH2 genes (Leukemia 2018;32:295)
Sample pathology report
  • Right posterior iliac crest, bone core biopsy and aspirate smear:
    • Acute myeloid leukemia with mutated RUNX1 (see comment)
    • Comment: The peripheral blood smear reveals pancytopenia with circulating blasts. The blasts are intermediate in size with high N:C ratio and variably prominent nucleoli. The marrow core biopsy and aspirate smear are packed with sheets of blasts which demonstrate minimal to no myeloid differentiation. Flow cytometry analysis of the marrow aspirate reveals the blast phenotype to be dim CD45, with expression of CD34 and CD13 and absence of B and T lineage markers. Next generation sequencing demonstrates the presence of a missense pathogenic RUNX1¬†mutation with a variant allele frequency of 65%. FISH panel and cytogenetic analysis are normal.
Differential diagnosis
Board review style question #1
Which of the following is the most common morphologic correlation (FAB) seen in AML with mutated RUNX1?

  1. M0
  2. M1
  3. M3
  4. M4
  5. M7
Board review style answer #1
Board review style question #2
Which of the following statements is true about AML with mutated RUNX1?

  1. ASXL1 and SRSF2 are the most commonly comutated genes
  2. Comutation with FLT3-ITD negates the poor prognostic impact of RUNX1
  3. Incidence is higher in people younger than 50 years
  4. It is associated with a better prognosis than AML with RUNX1-RUNX1T1 fusion
  5. It has lower frequency of CD34 positivity in blast cells than other subtypes of AML
Board review style answer #2
A. ASXL1 and SRSF2 are the most commonly comutated genes

Comment Here

Reference: AML with mutated RUNX1
Back to top
Image 01 Image 02