Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression

Abstract

CD56 high acute myeloid leukemias (AMLs) have a poor prognosis, but it has been unclear how CD56 expression is controlled and how it relates to clinical aggressiveness. We show that CD56 expression on AML cells correlates with an abnormal expression pattern of runtrelated transcription factor 1 (RUNX1) isoforms. Whereas full-length p48 RUNX1 (p48) up-regulated CD56 in AML cells, 3 previously unknown shorter RUNX1 isoforms, p38a, p30, and p24, suppressed CD56 expression. Both p48 and CD56 induced nuclear translocation of nuclear factor (NF) - IntroductionCD56 (NCAM-1) is a prototypic member of the family of Ca 2ϩ -independent cell adhesion molecules. 1 During development, CD56 is abundantly expressed in the fetal nervous system, 2 whereas after birth, various other tissues also express CD56. 3,4 In acute myeloid leukemias (AMLs), CD56 expression occurs in 15% to 20% of cases, particularly in the M2, M4, and M5 FrenchAmerican-British subtypes. CD56 positivity of leukemic blasts is an independent negative prognostic marker that is associated with a poor response to chemotherapy and with increased relapse rates, resulting in a shorter overall survival of affected patients. [5][6][7] Furthermore, clonal evolution of leukemic blasts with CD56 expression has been observed in originally CD56 Ϫ AMLs after relapse. 6,8 To date, however, it has been unclear what regulates CD56 expression on AML cells and how it is linked to the aggressive AML phenotype.We recently reported that the runt-related transcription factor 1, RUNX1 (AML1), controls CD56 expression in ischemic heart failure. 9 RUNX1 is also one of the most frequently mutated genes in AMLs. 10 Therefore, we hypothesized that RUNX1 might also regulate CD56 expression in AMLs, thereby controlling functional features of AML cells with relevance to their malignant potential. We show that multiple isoforms of RUNX1 were expressed in AML cells and that a characteristic pattern of expressed RUNX1 isoforms correlated with CD56 expression. Abnormal overexpression of the full-length p48 isoform in AML cells stimulated CD56 transcription, whereas 3 previously unknown RUNX1 isoforms, p38a, p30, and p24, suppressed it to a variable extent. Moreover, small inhibitory RNA (siRNA) directed against p48 RUNX1 suppressed CD56 expression and nuclear factor (NF)-B activation. Together, these findings suggest that strategies aimed at the balance between individual RUNX1 isoforms and/or NF-B signaling could inhibit the survival of CD56 high AML cells, thus providing promising new targets for therapy of this high-risk group of leukemias. Patients, materials, and methods Patients and control subjectsMyeloid blasts from 72 patients with acute myeloid leukemia, diagnosed according to the French-American-British study group (Table S1, available on the Blood website; see the Supplemental Materials link at the top of the online article) were isolated by fluorescent-activated cell sorting (CD33 ϩ /CD56 ϩ , CD33 ϩ /CD56 Ϫ ). Peripheral blood mononuclear cells from 12 normal healthy donors served a...

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“…Runx1, also known as acute myeloid leukemia-1, is significantly upregulated in several types of leukemia (Asou, 2003;Gattenloehner et al, 2007) as well as in breast cancer (Cancer Genome Atlas Network, 2012). Additionally, Runx1 upregulation is associated with progression of G1/S during cell cycle (Bernardin-Fried et al, 2004).…”

An evolutionarily conserved PTEN-C/EBPα-CTNNA1 axis controls myeloid development and transformation

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