Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript.
Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript.
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表达新型 MOZ-p300 融合转录本的先天性急性髓性白血病患者的深度自发分子缓解。
DOI：
10.1080/10428194.2018.1434885
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Yachie A.
中科院分区：
文献类型：
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作者：
Ikawa Y;Nishimura R;Maeba H;Fujiki T;Kuroda R;Noguchi K;Fukuda M;Mase S;Araki R;Mitani Y;Sato T;Terui K;Ito E;Kitabayashi I;Yachie A.
成人急性髓性白血病（AML）伴t (8; 16)（p11; p13）是一种罕见的预后较差的亚组。然而，Coenen等人[1]报道，17例先天性AML患者中有7例（8;16）（p11; p13）自发缓解，而其余10例患者在接受强化化疗后获得缓解。重要的是，7例自发缓解病例中有3例在没有化疗的情况下保持完全缓解，另外4例出现疾病复发（中位复发时间为17个月），这表明自发缓解病例可能处于深度完全缓解状态，迄今为止尚未通过更新的定量方法进行评估。因此，考虑到自发缓解主要发生在先天性AML病例中，在成人AML中很少有病例[2,3]，在治疗干预中，是“观察等待”政策还是强化化疗是至关重要的。涉及MOZ/MYST3基因（8p11）和CBP/CREBBP基因（16p13）的t (8; 16)（p11; p13）易位与AML[4]的FAB M4/M5亚型相关。MOZ还与编码CBP同源物p300 （22q13）、TIF2 [inv (8)(p11q13)]及其同源物NCOA3[5-8]的基因融合。然而，到目前为止，这些基因融合与自发性缓解的关联还没有报道。p300在氨基酸水平上与CBP有63%的同源性，在结构和功能上与CBP相似，两种蛋白都在转录和染色质动力学调节中发挥复杂的作用[9]。因此，涉及CBP和p300的MOZ重排可以驱动类似的病理生理。事实上，已有3例成人AML患者被描述为MOZ-p300重排[7,8]，其临床表型与MOZ-CBP重排病例相似，与无自发缓解的不良预后AML （M4/M5）一致。在这里，我们报告了第一例先天性AML自发性缓解的at (8; 22)（p11; q13）易位，涉及一种新的MOZ-p300融合。我们还发现自发性缓解比强化化疗后的缓解更深。一个新生女孩在出生后1天出现多个皮肤结节。外周血分析显示白细胞计数54.93 x109/L， 50%原细胞，血红蛋白水平17.3 g/dL，血小板计数143x109/L。骨髓穿刺显示44%的母细胞样未成熟单核细胞。表面标记分析显示白血病细胞表达CD11b、CD13和CD33，诊断为AML （FAB M5b）。骨髓细胞的细胞遗传学分析显示核型异常46，XX, t (8; 12; 22)（p11）。2;抓起。1;q13)在20个中期中的15个（图1 (A)）。为了检测MOZ-p300融合转录物是否表达，我们进行逆转录聚合酶链反应（RT-PCR）分析。对扩增片段的序列分析发现了一个新的帧内MOZ-p300融合转录物，涉及MOZ外显子16和p300外显子6（图1 (B)）。皮肤活检显示弥漫性真皮浸润白血病细胞，其表型与骨髓中的原细胞相同。由于皮肤结节逐渐自发消退，患者总体情况良好，我们采取观察等待方法，未进行化疗，患者于3个月大时完全缓解。为了评估完全缓解的深度，骨髓样本中的最小残留病（MRD）用MOZ和p300基因的引物/探针集使用液滴数字PCR （ddPCR）进行定量，据报道，这是一种更敏感的监测方法。
Adult acute myeloid leukemia (AML) with t (8; 16)(p11; p13) is a rare subgroup with a poor prognosis. However, Coenen et al.[1] reported that spontaneous remission occurred in 7 of 17 congenital AML cases with t (8; 16)(p11; p13), whereas the remaining 10 cases achieved remission after receiving intensive chemotherapy. Importantly, three of the seven spontaneously remittent cases remained in complete remission without chemotherapy, and the other four cases suffered disease recurrence (median time to recurrence 17 months), suggesting that the spontaneously remittent cases might be in deep complete remission, which has not been evaluated by updated quantitative methods to date. Thus, considering that the spontaneous remission would occur mainly in congenital AML cases, there are few cases in adult AML [2, 3] where the decision of therapeutic intervention whether a “watch and wait” policy or an intensive chemotherapy is critical. The t (8; 16)(p11; p13) translocation involving the MOZ/MYST3 gene (8p11) and the CBP/CREBBP gene (16p13) is associated with the FAB M4/M5 subtype of AML [4]. MOZ is also fused to genes encoding the CBP homolog, p300 (22q13), and TIF2 [inv (8)(p11q13)] and its paralogue NCOA3 [5–8]. However, associations of these gene fusions with spontaneous remission have not been reported so far. p300, which is 63% homologous to CBP at the amino-acid level, is structurally and functionally similar to CBP and both proteins play complex roles in the regulation of transcription and chromatin dynamics [9]. Therefore, MOZ rearrangements involving CBP and p300 could drive a similar pathophysiology. In fact, three adult AML cases with MOZ-p300 rearrangements have been described [7, 8], with clinical phenotypes consistent with poor prognosis AML (M4/M5) without spontaneous remission, similar to the cases with MOZ-CBP rearrangements.Here, we report the first case of spontaneous remission of congenital AML with at (8; 22)(p11; q13) translocation involving a novel MOZ-p300 fusion. We also found that the spontaneous remission was deeper than that achieved after intensive chemotherapy. A newborn girl presented with multiple skin nodules 1day after birth. Peripheral blood analysis showed a white blood cell count of 54.93 x109/L with 50% blasts, a hemoglobin level of 17.3 g/dL, and a platelet count of 143x109/L. Bone marrow aspiration revealed 44% blastlike immature monocytic cells. Surface marker analysis showed that leukemic cells expressed CD11b, CD13, and CD33, and a diagnosis of AML (FAB M5b) was made. Cytogenetic analyses of bone marrow cells revealed an abnormal karyotype of 46, XX, t (8; 12; 22)(p11. 2; q24. 1; q13) in 15 out of 20 metaphases (Figure 1 (A)). To test whether the MOZ-p300 fusion transcript was expressed, reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed. Sequence analysis of the amplified fragment detected a novel in-frame MOZ-p300 fusion transcript, involving MOZ exon 16 and p300 exon 6 (Figure 1 (B)). A skin biopsy revealed a diffuse dermal infiltration by leukemic cells that had the same phenotype as the blasts in the bone marrow. Since the skin nodules spontaneously regressed gradually, and the patient was in good general condition, we took a watch and wait approach without chemotherapy, and the patient achieved complete remission by 3 months of age. To evaluate the depth of complete remission, minimal residual disease (MRD) in the bone marrow sample was quantified with the primer/probe set for the MOZ and p300 genes using droplet digital PCR (ddPCR), which is reported to be a more sensitive monitoring …