ASXL1 mutation as a surrogate marker in acute myeloid leukemia with myelodysplasia‐related changes and normal karyotype

Abstract

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) are poor outcome leukemias. Its diagnosis is based on clinical, cytogenetic, and cytomorphologic criteria, last criterion being sometimes difficult to assess. A high frequency of ASXL1 mutations have been described in this leukemia. We sequenced ASXL1 gene mutations in 61 patients with AML-MRC and 46 controls with acute myeloid leukemia without other specifications (AML-NOS) to identify clinical, cytomorphologic, and cytogenetic characteristics associated with ASXL1 mutational status. Mutated ASXL1 (ASXL1+) was observed in 31% of patients with AML-MRC compared to 4.3% in AML-NOS.Its presence in AML-MRC was associated with older age, a previous history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/ MPN), leukocytosis, presence of micromegakaryocytes in bone marrow, lower number of blasts in bone marrow, myelomonocytic/monocytic morphological features and normal karyotype. ASXL1 mutation was not observed in patients with myelodysplastic syndrome-related cytogenetic abnormalities or TP53 mutations. Differences in terms of overall survival were found only in AML-MRC patients without prior MDS or MDS/ MPN and with intermediate-risk karyotype, having ASXL1+ patients a worst outcome than ASXL1−. We conclude that the ASXL1 mutation frequency is high in AML-MRC patients being its presence associated with specific characteristics including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML-MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML-MRC with intermediate-risk karyotype. K E Y W O R D S AML-MRC, ASXL1, myelodysplasia, myeloid leukemia 3638 | PRATS-MARTÍN eT Al.

Network-based clustering unveils interconnected landscapes of genomic and clinical features across myeloid malignancies

“…Our network elucidates interconnections of -7/del(7q) with various genomic and clinical features, corroborating its relevance in MDS classification and prognosis. The ASXL1 mutation is highly connected to various other mutations in our network and has been previously found to be associated with adverse outcomes in MDS patients 36 . Notably, our network displays interconnections among ASXL1, SRSF2 , and RUNX1 .…”

A confirmation of ASXL1 as biological marker of normal cytogenetic acute myeloid leukemia with myelodysplasia-related changes (AML-MRC): A case successfully treated with CPX-351

“…It's known that ASXL1 mutations have an higher frequency in AML-MRC than other AML (35% vs 10.8-14.5%) [7][8][9]. Prats-Martin et al analysed ASXL1 gene mutations in 61 patients with AML-MRC and 46 controls with AML Without Other Specifications (AML-NOS) confirming the higher frequency of ASXL1 mutations in patients with AML-MRC (31%), compared to control group of patients with AML-NOS (4.3%) [10].…”

“…They identified clinical, cytomorphological, cytogenetic features associated with AML-MRC ASXL1+ such as: higher leukocyte count at diagnosis (p=0.005), higher frequency of micromegakaryocytes (p=0.031) with a trend toward a higher presence of megakaryocyte dysplasia (≥50%) (p=0.071), a lower number of blasts in bone marrow (p=0.009) with myelomonocitic/monocitic morphological features (p=0.001), absence of cytogenetic abnormalities related to myelodysplasia and TP53 mutations (p.035) [9,6,10]. Up to 56% of patients with AML-MRC, displaying a normal karyotype, were ASXL1+ [10]. This morphological and biological pattern is similar to that observed in our patient, a part from leukocytopenia.…”

“…Similar leukemia is unfortunately characterised by a poor prognosis with a median OS of 1.5 months vs 9 to 12 months in those patients eligible to intensive induction chemotherapy [11][12][13]. In Prats-Martin retrospective analysis ASXL1+ and ASXL1-AML-MRC showed respectively 100 days vs 362 days median overall survival [10].…”

Clinical characteristics and prognosis analysis of patients with de novo ASXL1‐mutated AML treated with the C‐HUNAN‐AML‐15 protocol: A multicenter study by the South China Pediatric AML Collaborative Group

“…However, in recent years, with the advent of cytogenetic and molecular biology tests to provide a basis for risk stratification of pediatric AML and timely initiation of appropriate treatment, the survival rate of pediatric AML has been improved. A meta‐analysis reported that 6%–30% ASXL1 mutation were found in AML cases, a gene located in the chromosome region 20q11 that encodes a protein of the polycomb group and trithorax complex family to maintain gene expression homeostasis 3,4 . Xia's study 5 revealed a new mechanism by which ASXL1 mutations promote cancer, in myeloid neoplasm, the ASXL1 mutant protein, although still able to bind to BAP1, has lost its ability to interact with FOXK1/K2, resulting in an impaired function that regulates the growth of leukemia cells.…”