Acute myeloid leukemia with t(10;17)(p15;q21)/ ZMYND11::MBTD1: a subtype with minimal differentiation, CD7/CD56 expression, and generally poor outcomes in adults

The t(10;17)(p15;q21) resulting in the ZMYND11::MBTD1 is a rare but recurrent cytogenetic abnormality previously reported in approximately 10 cases of acute myeloid leukemia (AML), predominantly in AML with minimal differentiation (also known as M0).^1-5 Prior studies have noted frequent expression of CD7 and CD56 in these cases. However, due to the limited number of reported cases, the clinicopathologic characteristics, gene mutation profiles, treatment responses, and patient outcomes associated with ZMYN-D11::MBTD1 remain poorly understood. In this study, we describe 5 additional cases of AML harboring t(10;17)(p15;q21) with comprehensive clinicopathologic, immunophenotypic, cytogenetic and molecular characterization. We also summarize the findings from 7 previously reported cases in the literature. This study was approved by the Institutional Review Board of the MD Anderson Cancer Center and was conducted in accordance with the principles of the Declaration of Helsinki.

Demographic, clinicopathologic, cytogenetic and molecular findings are summarized in Table 1. All 5 patients presented with AML characterized by primitive blasts showing minimal differentiation. Flow cytometric immunophenotypic profiles are summarized in Table 2. In all cases, the blasts were uniformly positive for CD7, CD33, CD56 (bright) and CD117, and were negative for myeloperoxidase (MPO), monocytic markers (CD4, CD14, CD64), CD19, and the T-cell markers (CD2, sCD3, cytoCD3, CD5). HLA-DR was completely absent in 4 cases and minimally expressed in one case. Cytochemical staining for MPO was negative or showed reactivity in less than 3% of blasts in all cases. All cases had a non-complex karyotype and in 4 cases no mutations were identified.

Patient 1 presented with fatigue and fever. Bone marrow (BM) aspiration revealed 58% blasts. The blasts were medium to large, with scant cytoplasm, fine chromatin, distinct nucleoli, and without Auer rods (Figure 1A, B). Flow cytometric immunophenotyping (FCI) results are shown in Figure 1C and summarized in Table 2. Conventional karyotyping revealed t(10;17)(p15;q21) as the sole abnormality (Figure 1D). The patient was diagnosed with AML with minimal differentiation (M0) and received induction chemotherapy. He achieved complete remission at three months but relapsed at 23 months. Optical genome mapping (OGM) confirmed t(10;17)(p15.3;q21.33)(244532;51223617) and detected a fusion gene ZMYND11::MBTD1 (Figure 1E, F). The patient received multiple lines of salvage therapy but was refractory to all of them and died 34 months after diagnosis.

Patient 2 had a history of breast cancer (diagnosed 9 years prior) treated by mastectomy and hormonal therapy. She presented with fatigue and a 16-pound weight loss over several months. BM aspiration and biopsy showed sheets of neoplastic cells that appeared “cohesive” on aspirate smears. Immunohistochemistry and FCI showed that the neoplastic cells were strongly positive for CD7, CD33, CD43, CD56 and CD99, weak CD117, and negative for MPO, HLADR, all other lineage-specific markers and cytokeratin. OGM detected a t(10;17)(p15.3;q21.33) with the fusion gene ZMYND11::MBTD1. The patient was treated with venetoclax, cladribine and low-dose cytarabine. However, persistent disease was noted at the 1-month follow up and the patient was lost to follow-up two months later.

Patient 3 was diagnosed with AML harboring chromosomal translocation t(10;17) and TET2 mutation. She received standard 7+3 induction chemotherapy and achieved morphologic remission at the 1-month BM evaluation. She underwent hematopoietic stem cell transplant (HSCT) at eight months post diagnosis. Unfortunately, she relapsed three months post HSCT. After relapse, the patient was refractory to salvage therapies and died four months after relapse.

Patient 4 was diagnosed with AML with cytogenetic abnormalities of t(10;17) and del(16q). He received standard 7+3 induction chemotherapy and had achieved complete remission at the 1-month follow-up. The patient subsequently underwent first HSCT at four months post diagnosis. However, he relapsed at 30 months with recurrence of the same chromosomal abnormalities. The patient was treated with mitoxantrone plus VP-16 and achieved a second remission, followed by a second HSCT at 36 months. Unfortunately, he relapsed again at 45 months. Karyotyping revealed clonal evolution with a newly acquired inv(2)(p11.2q21). Following second relapse, the patient was refractory to multiple lines of salvage therapy and died 57 months after diagnosis.

Patient 5 was diagnosed with AML with t(10;17). She received four cycles of azacitidine, but persistent disease was noted. The patient was later managed at her local hospital, where details of her subsequent therapy and disease status were unavailable. She died 11 months after initial diagnosis.

ZMYND11 (chr 10p15) has 14 exons and MBTD1 (chr 17q21) has 17 exons. The t(10;17)(p15;q21) produces an in-frame chimeric fusion, joining ZMYND11 exons 1-12^2,4,5 (less often exon 1-11³) with MBTD1 exons 3-17.^2-5 In this cohort, OGM revealed breakpoints on ZMYND11 between exons 9-13 and on MBTD1 between exons 3-4 in two cases. The fusion protein retained the N-terminal chromatin reader domains of ZMYND11 (PHD, bromodomain and PWWP) which recognizes H3.3K36me3 at transcriptional active loci.⁶ MBTD1 contributes components of the NuA4/TIP60 histone acetyltransferase complex, a transcriptional co-activator.⁷ ZMYND11::MB-TD1 misdirects TIP60 to ZMYND11-bound loci, leading to aberrant histone acetylation, transcriptional upregulation, and altered RNA splicing,^8,9 including activation of MYC. In mouse models, ZMYND11::MBTD1 enforces a pro-leukemic stem-like gene-expression program, including upregulation of pro-oncogenic transcription factors such as HOXA, MEIS1, SOX4, MYC and MYB.^8,9 Most cases with ZMYND11::MBTD1 exhibit a simple or non-complex karyotype even at relapse, and gene mutations are rare. These findings suggest that ZMYND11::MBTD1 is a very potent leukemogenic driver in AML and does not require additional co-operating mutations. Acute myeloid leukemia with t(10;17)/ ZMYND11::MBTD1 is a rare but recurrent cytogenetic abnormality, with only 6 confirmed cases reported in the literature to date (cases #6-11 in Tables 1 and 2).^1-5,10 One additional case (#12) with t(10;17) exhibited a distinctive immunophenotype highly suggestive of ZMYND11::MBTD1 although the fusion was not confirmed.¹¹ Three other AML cases with t(10;17)(p15;q21) have been described; however, these cases lack confirmation of the fusion and detailed immunophenotypic characterization.^12-14 Although t(10;17)(p15;q21) is readily identifiable by conventional chromosomal analysis, confirmation of the ZMYND11::MBTD1 may be challenging because these genes are not typically included in targeted RNA sequencing panels. Furthermore, fluorescence in situ hybridization (FISH) probes for this fusion are not routinely available in clinical cytogenetics laboratories. Prior studies have used bacterial artificial chromosome (BAC) FISH probes (RP11-10D13 and RP11-379D19)¹ or RT-PCR to detect this fusion.^2-5 In the current cohort, the fusion was identified by OGM. Greater awareness of the distinctive cytogenetic and immunophenotypic features associated with this fusion may help recognize this entity when t(10;17)(p15;q21) is observed on chromosomal analysis.

Table 1.Demographic, clinicopathologic, cytogenetic and molecular findings.

Figure 1.Morphologic, flow cytometric immunophenotyping, karyotyping and optical genome mapping findings in case #1. (A) Bone marrow (BM) core biopsy specimen (400x) exhibits sheets of immature-looking cells with distinct / prominent nucleoli. (B) BM aspirate smear (1000x) shows that the blasts are of intermediate size with scant cytoplasm, immature chromatin and distinct nucleoli. (C) CD45 dim (~70% of total events) cells were CD7⁺/CD13^+dim/CD14^-/CD33⁺/CD34⁺/CD38^decreased/CD56^+bright/CD64^-/CD117⁺/ CD123^+dim/HLA^-DR^-/MPO^-. (D) G-banded chromosomal analysis shows t(10;17)(p15;q21). Arrows indicate abnormal chr10 and chr17 with t(10;17). (E) Circos plot of optical genome mapping shows t(10;17) as the sole abnormality. (F) Genome browser of optical genome mapping demonstrates a fusion gene ZMYND11::MBTD1 that arose via t(10;17). The middle blue bar represents the chimeric DNA fragment generated from t(10;17).

Table 2.Immunophenotypic findings.

Morphologically, the blasts were poorly differentiated, displaying primitive morphology and lacking cytoplasmic granules. In some cases, including case #2 and a previously reported case,⁴ the blasts formed clusters, mimicking solid tumor involvement in the BM. Immunophenotypically, the blasts were positive for CD7 (12/12), CD33 (12/12), CD56 (11/11), and CD117 (11/11), negative for HLA-DR (8/10) or positive in small subset (2/10), and negative for MPO (9/9). Of note, CD7 and CD56 expression could raise the possibility of the differential diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN); however, the absence of CD4 and bright CD123 expression makes BPDCN unlikely.

Clinically, most patients presented with de novo AML with anemia, thrombocytopenia and normal or low white blood cell counts, without reported extramedullary disease. Although some patients achieved initial remission following intensive chemotherapy, most experienced early relapse.^2,5,10 Notably, 2 pediatric patients (#6 and #12) achieved long-term remission. Four patients (#3-4, #7-8) underwent HSCT but all subsequently relapsed. Responses to salvage regimens after relapse were generally poor, emphasizing the urgent need for novel therapeutic approaches.

In conclusion, AML with t(10;17)/ZMYND11::MBTD1 appears to represent a distinct subtype of AML that may warrant recognition as a separate entity under the category of “other rare recurrent genetic abnormalities” in future AML classification systems. The blasts typically have primitive morphologic features, with uniform expression of CD7 and CD56, and absence of HLA-DR and MPO. Genetically, patients often harbor t(10;17) as the sole abnormality or have a non-complex karyotype, with a paucity of co-occurring gene mutations. Further studies in larger cohorts are needed to better understand the biology of this entity and to identify effective therapeutic strategies to improve patient outcomes.

Footnotes

• Received July 21, 2025
• Accepted November 11, 2025

Correspondence

G. TANG - gtang@mdanderson.org

Disclosures

No conflicts of interest to disclose.

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