Treating AML with ATRA? Beware MN1!

MN1 overexpression is a negative predictive factor for elderly AML patients receiving ATRA treatment.

The paper by Heuser and colleagues in this issue of Blood identifies MN1 as a marker that predicts significantly prolonged event-free survival in elderly patients with acute myeloid leukemia (AML) who receive all-trans retinoic acid (ATRA). The MN1 gene encodes a transcriptional coactivator of the retinoic acid and vitamin D nuclear receptors.¹  Patients with AML (except those with M3-AML) who expressed low levels of MN1 and received ATRA fared significantly better than those who did not receive ATRA or patients who expressed high levels of MN1 and did or did not receive ATRA. The authors also show that MN1 is an efficient myeloid oncoprotein; its overexpression in mouse bone marrow rapidly induced AML, suggesting the potential for a similar role in human AML.

These observations are not the first to link MN1 with myeloid disease in humans. The MN1 gene was originally identified as the candidate meningioma tumor suppressor gene on chromosome 22²  but is also the target of the balanced chromosome translocation t(12;22)(p13;q12) in human myeloid malignancies.³ MN1 is fused to TEL1 (ETV6), which encodes an ETS transcription factor. The MN1-TEL fusion protein exhibits oncogenic activity in primary mouse bone marrow cells and, in conjunction with HOXA9, predisposes mice to AML, a combination mimicking the situation in patients with t(12;22).⁴ 

MN1 overexpression was first noticed in the pediatric and adult M4-AML subtype, specified by the inv16 chromosomal aberration, which was confirmed by Carella et al.⁵  The encoded CBFb-MYH11 fusion gene is a dominant-negative regulator of the CBF transcription factor. In a paper published concurrently with the one discussed here, Carella and coworkers⁵  confirm MN1's oncogenicity in the mouse hematopoietic system and also show that MN1 overexpression strongly cooperates with CBFb-MYH11 in a mouse model of inv16 AML. Together, these data put MN1 firmly on the map of oncogenes to be reckoned with in human AML.

How does MN1 work? Given that RAR/RXR recruits MN1 via the transcriptional coactivator p300/CBP,¹  the article by Heuser and colleagues lifts a tip of the veil by showing that MN1 inhibits ATRA-induced differentiation of myeloid progenitors. Their data suggest that the differentiation block is caused by a dominant-negative effect of MN1 on RAR/RXR (see figure), which is released when MN1 is fused to the VP16 transcription-activating domain. Given that MN1-VP16 does not interfere with MN1's growth-promoting activity, growth might be mediated via other transcription factors. Through its interaction with p300/CBP, MN1 may affect the activity of multiple myeloid transcription factors that recruit p300/CBP, all of which help to regulate the growth and differentiation of myeloid progenitors (see figure). Therefore, to fully comprehend the role of MN1 in bone marrow and the detrimental effects of MN1 overexpression, extensive biochemical and biologic analyses are needed to identify these myeloid transcription factors. This, in turn, may lead to the design or discovery of substances that interfere with MN1's ability to interact with these transcription factors. The study by Heuser and colleagues strongly suggests that patients whose AML cells overexpress MN1 and are not responsive to ATRA treatment could greatly benefit from treatment with such substances.