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The combination of C-Myc rearrangement and 1q21 gain is associated with poor prognosis in multiple myeloma

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Abstract

The prognostic value of chromosomal 1q21 gain in newly diagnosed multiple myeloma (NDMM) remains controversial. Add-on Myc aberrations may further worsen the outcome. To investigate whether specific genes located at the 1q21 region, such as myeloid cell leukemia 1 (Mcl-1), are involved in NDMM progression, we examined bone marrow cytogenetic abnormalities in 153 patients with NDMM by fluorescence in situ hybridization. Their response to treatment and survival was also analyzed. C-Myc and Mcl-1 expressions in bone marrow samples were analyzed by RT-PCR. The expression of Mcl-1 was evaluated in bone marrow sections by immunohistochemistry. MM cell lines were transfected with Mcl-1 siRNA. 1q21 gain was present in 55/153 (35.9%) patients and strongly associated with Myc rearrangement (31/153, 20.3%, P = 0.004). A positive correlation was observed between Myc and Mcl-1 mRNA levels in bone marrow cells from 47 patients (r = 0.57, P < 0.001). The combination of 1q21 gain and Myc rearrangement was associated with poorer overall survival than Myc rearrangement alone (16.8 vs. 27.9 months, P = 0.077) or 1q21 gain alone (16.8 vs. 60.7 months, P < 0.01). High Mcl-1 protein expression in bone marrow plasma cells was associated with Myc rearrangement. Mcl-1 silencing by siRNA inhibited Myc protein expression in three myeloma cell lines. Treatment with the small-molecule Mcl-1 inhibitor, UMI-77, produced similar results. Overall, the combination of Myc rearrangement and 1q21 gain was associated with particularly poor prognosis in patients with MM. Furthermore, our data are consistent with Mcl-1-dependent Myc protein activation.

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Abbreviations

EMD:

extramedullary disease

FISH:

fluorescence in situ hybridization

IMWG:

International Myeloma Working Group

ISS:

International Staging System

LDH:

elevated lactic dehydrogenase

Mcl-1:

myeloid cell leukemia 1

MM:

multiple myeloma

MNCs:

mononuclear cells

NDMM:

newly diagnosed MM

OS:

overall survival.

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Acknowledgments

We acknowledge the assistance of the Department of Pathology, Peking Union Medical College Hospital, for the preparation of bone marrow sections.

Funding

This work was supported by the Natural Science Funds of the Beijing Municipality [No 7192175] and the CAMS Initiative for Innovative Medicine [Grant Nos. 2016-I2M-3-025].

Author information

Author notes

  1. Yuanyuan Jin and Xiaochen Yu contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China

    Yuanyuan Jin, Xiaochen Yu, Jianhua Du, Hui Li, Yunyan Zan, Miao Chen, Yanbin Zhang, Minhong Yu, Daobin Zhou & Junling Zhuang

  2. Department of Hematology, People’s Hospital of Jiangsu Province, Nanjing, China

    Yuanyuan Jin

  3. Department of Hematology, West China Hospital, Sichuan University, Chengdu, China

    Wenjiao Tang

  4. Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Congwei Jia

  5. Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Weiqi Rong

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  1. Yuanyuan Jin
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Contributions

Y.J. and X.Y. contributed equally to this article as first authors, wrote the article, and analyzed the clinical and experimental data. Y.Z. isolated the PBMCs from the bone marrow. H.L. contributed to the FISH experiments. W.T. contributed to patients’ follow-up. C.J. stained bone marrow slides and trained Y.J., M.Y., and Y.Z. collected the clinical data. W.R. was involved in statistical analysis. D.Z. and M.C. participated in manuscript preparation and revision. J.Z. is the corresponding author and contributed to the study design. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Junling Zhuang.

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All human samples were obtained in accordance with the guidelines of the Ethics Committee of the Peking Union Medical College Hospital & Chinese Academy of Medical Sciences & Peking Union Medical College.

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The authors declare no competing interests.

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Jin, Y., Yu, X., Du, J. et al. The combination of C-Myc rearrangement and 1q21 gain is associated with poor prognosis in multiple myeloma. Ann Hematol 100, 1251–1260 (2021). https://doi.org/10.1007/s00277-021-04475-2

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  • DOI: https://doi.org/10.1007/s00277-021-04475-2

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