A pediatric case of acute myeloid leukemia with KMT2A gene rearrangement t(10;11) and 16p11.2 microdeletion syndrome

To the Editor: Overall survival for pediatric patients with acute myeloid leukemia (AML) is 60-70%; however, survival is dismal among certain patient subgroups.1,2 Cytogenetic mutations and genetic syndromes are associated with the development of AML with varying outcomes.3–5 We report the first patient diagnosed with AML and 16p11.2 microdeletion syndrome coexistent with KMT2A gene rearrangement. 16q11.2 microdeletion syndrome is associated with developmental delay, intellectual disability, and autism spectrum disorder.6 Interestingly, 16p11.2 contains the mitogen-activated protein kinase 3 (MAPK3) gene, which regulates several cellular pathways, as well as the major vault protein (MVP) gene, whichmay be related to chemoresistance.7–9 At the time of diagnosis, the patient was a 12-year-old multiracial female with developmental delay, short stature, and coarse facial features who presented with gingival hyperplasia, weight loss, and fatigue. Initial laboratory investigations showed leukocytosis (WBC 70 500/μL), anemia (hemoglobin 6.4 g/dL), and thrombocytopenia (platelet count 123 000/μL). Prothrombin time, partial thromboplastin time, and fibrinogen levels were normal. Peripheral blood flow cytometry evaluation revealed a CD45 dim myeloblast population with monocytic differentiation comprising 27% of the cells. Bone marrow aspiration and biopsy confirmed an increased CD34/CD117/CD14/CD33 positive blast population comprising 59% of the cells. The cerebrospinal fluid analysis was significant for nine nucleated cells and positive for blasts. Cytogenetic analysis of the bone marrowrevealedKMT2Agene rearrangement t(10;11)(p11.2;q23q13), alternatively known as mixed lineage leukemia (MLL) gene rearrangement (gene/locus MIM#159555). Chromosomal microarray showed a 754 kb interstitial deletion of arr[hg19]16p11.2(29,567,29530,321,320)x1. She was diagnosed with AML with KMT2A gene rearrangement with central nervous system involvement and 16p11.2 microdeletion syndrome. She was administered induction chemotherapy with high-dose cytarabine, daunorubicin, and etoposide with intrathecal cytarabine. Minimal residual disease (MRD) was negative after the first induction with no detection of KMT2A rearrangement. She subsequently received mitoxantrone and high-dose cytarabine followed by intensification with high-dose cytarabine and etoposide. She tolerated the induction therapy well, and because her particular KMT2A rearrangement was associated with a poor prognosis, she subsequently underwent allogeneic stem cell transplantation (SCT).10–12 Due to the lack of any matched sibling donor, she received a haploidentical SCT from her mother. She was conditioned with melphalan, thiotepa, and fludarabine followed by posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil for graft versus host prophylaxis. Her course was complicated by mild sinusoidal obstructive syndrome treatedwithN-acetyl cysteine and ursodeoxycholic acid. Bonemarrow aspiration posttransplant day+56 showed restriction fragment length polymorphism (RFLP) > 97% donor with negative MRD, as did her day +104 marrow. She developed mild acute and subsequently chronic graft versus host disease of the skin, which improved significantly with topical steroid. The patient has been clinically well, has been off immunosuppression since 11 months post haplo-SCT, and remains in remission approximately 21months posttransplantation. The patient’s microdeletion includes a missing allele for both MVP andMAPK3 genes. TheMVP gene is locatedwithin chromosome region 16p11.2 and its product is also known as lung resistance-related protein, which was first discovered as a new 110 kD drug transporter in doxorubicin-resistant lung cancer cells in 1995.13 The protein is thought to transport cytotoxic DNA-targeting drugs and mediate primary chemoresistance.14 Previous reports have shown that high expression of MVP mRNA may predict poor early response to induction chemotherapy in acute lymphoid leukemia in children, whereas anti-MVP monoclonal antibodies were found to increase cellular cisplatin levels and induce chemosensitivity in ovarian cancer.15,16 Furthermore, whole-exome sequencing of paired diagnosis and relapse samples from children with AML identified MVP as a new mutation in relapsed patients, whichmay contribute to chemoresistance.17 MAPK3 is also located within the chromosome region 16p11.2 and encodes extracellular signal-regulated kinase 1 (ERK1). ERKs are one of the major intracellular signals, which are activated by a variety of extracellular agents including hormones, growth factors, and cellular stress, and induce cellular processes such as proliferation and differentiation. ERK1 plays a central role in cell proliferation control by inducing positive regulators of the cell cycle. It is activated by factors such as mitogens, cytokines, macrophage colony-stimulating factor, and other growth factors.18,19 Additionally, ERK1 plays a major role in the regulation of differentiation and proliferation in myeloid cells and has been reported to be activated in AML.20 Here, we report the first case of a patient with 16p11.2 microdeletion syndrome and the development of AML. Besides monocytic differentiation and extramedullary involvement, this patient did not exhibit any of the other adverse clinical features reported to be associated with t(10;11) KMT2A translocation, including leukocytosis,