Family Aggregation of Hematological Malignancies Discovered from an Acute Myeloid Leukemia Patient with STK11 and THBD Gene Mutation Open Access

Acute myeloid leukemia (AML) is a large class of heterogeneous hematological malignancies with the highest incidence rate in acute leukemia. The overall prognosis is poor, and the 5-year overall survival rate is about 28% [1, 2]. Its pathogenesis is still unclear, which may be related to genetics. According to the latest AML NCCN guidelines, genes involved in AML family genetic changes include RUNX1, ANKRD26, CEBPA, DDX41, ETV6, GATA2, MBD4, MECOM/EVI1, SAMD9/SAMD9L, TERC/TERT, and ATG2B/GSKIP. Finding new genes related to AML genetics is of great significance for predicting the prognosis of patients, developing targeted drugs, and selecting transplant donors.

Here, we report a case of adult female AML patient whose three relatives suffered from hematological malignancies, including Waldenstrom macroglobulinemia, NK/T-cell lymphoma, and angioimmunoblastic T-cell lymphoma. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000532003). During the process of searching for suitable transplant donors, we screened for genetic susceptibility genes related to blood and immune system diseases, and found that the patient herself, her son, her daughter, and her two cousins all had STK11 p.F354L and/or THBD p.D486Y mutations. Since 3 relatives of the patient had hematological malignancies, and this patient herself and her four relatives all had STK11 and/or THBD mutations, we consider that STK11 and THBD may be related to family genetic changes which ultimately cause the family aggregation of hematological malignancies. At present, there is no research or case report on the relationship between STK11/THBD and family aggregation of hematological malignancies. We report for the first time that an AML patient with STK11 and THBD mutations has a family aggregation of hematological malignancies.

A 38-year-old female patient was diagnosed as having “CBFbeta-MYH11-positive AML with NRAS/LNK mutation” in May 2021. Bone marrow smears showed 20% of primordial granulocytes and 24.5% of promyelocytes. Flow cytometry of bone marrow showed that 39.5% of the nuclear cells were abnormal primitive cells. The karyotype was 46, XX, inv (16) (p13q22) [20]. The fusion gene was found to be CBFbeta-MYH11-positive. NRAS and LNK were mutated, with mutation frequencies of 43.2% and 47.9%, respectively. After a course of IDA (idarubicin and cytarabine) chemotherapy, the patient was evaluated as morphologically complete remission and minimal residual disease (MRD) positive (CBFbeta-MYH11 quantitative was 0.09%). After 2 cycles of high-dose cytarabine and 1 cycle of BCL2 inhibitor + azacitidine chemotherapy, MRD was still positive (CBFbeta/MYH11 quantitative was 0.2%). After the follow-up oral treatment of BCL2 inhibitor + dasatinib, MRD turned negative and then became positive again. Twice lumbar puncture and intrathecal injection operations were performed during this period, and no abnormal cells were found in the cerebrospinal fluid.

In the process of asking about the family history of the patient, we found that there were 3 patients with hematological malignancies in the patient’s family, including two sisters and 1 brother of the patient’s father. The patient’s father’s two sisters have Waldenstrom macroglobulinemia and NK/T-cell lymphoma, respectively, and one brother has angioimmunoblastic T-cell lymphoma (Fig. 1). Considering the possible family aggregation history of hematological malignancies of this patient, we screened genetic susceptibility genes related to blood and immune system diseases in order to find suitable transplant donors, and found that the patient herself, her son, her daughter, and her two cousins all had STK11 p.F354L and/or THBD p.D486Y mutations (Fig. 1). At present, the patient is undergoing continuous treatment and preparing for allogeneic hematopoietic stem cell transplantation.

THBD gene is located in the first band of the short arm 1 region of chromosome 20 and encodes thrombomodulin, which is an endothelium-specific type 1 membrane receptor. The junction of thrombomodulin and thrombin lead to the activation of protein C, which in turn degrades coagulation factors Va and vllla. The abnormal function of thrombomodulin is related to the susceptibility to atypical hemolytic uremic syndrome (aHUS) and thrombosis. Among them, the susceptibility of aHUS is mostly manifested as autosomal dominant inheritance. THBD p.D486Y mutation can cause aspartic acid at 486 position to become tyrosine, which is related to the susceptibility of aHUS. Besides aHUS, a study reported that THBD mutation exists in families with bleeding events [3]. In AML, it has been reported that recombinant human soluble thrombomodulin can be used to treat AML patients with DIC [4‒6]. Kojima et al. [7] reported that recombinant human soluble thrombomodulin can prevent retinoic acid-related differentiation syndrome. At present, there is no report on the correlation between THBD and the pathogenesis of AML.

STK11 gene is located in the third band of the short arm 1 region of chromosome 19, and it encodes a protein that is a member of the serine/threonine kinase family. STK11 gene plays a role in cell metabolism, polarity, apoptosis, and DNA damage response, and its functional abnormalities are related to breast cancer, ovarian cancer, NSCLC, melanoma, juvenile polyp syndrome, and Peutz-Jeghers syndrome (PJS) [8]. Among them, PJS is clinically autosomal dominant inheritance. STK11 p.F354L mutation can cause phenylalanine at 354 position to become leucine. STK11 p.F354L mutation was detected in PJS patients, which led to the loss of cell polarity and the decrease of AMPK activity, thus affecting the downstream pathway of AMPK [9]. It is speculated that this mutation is related to the development of malignant tumors [9]. Besides PJS, STK11 has also been reported to be genetically related to pancreatic cancer [10, 11] and breast cancer [12] families.

A clinical retrospective analysis has reported that a pathogenic polymorphism Phe354Leu of STK11 is detected in 7% of 85 AML patients, and patients with Phe354Leu polymorphism diagnosed at younger ages had a worse overall survival [13]. Some basic studies have also reported the role of STK11 in AML. For example, Green et al. [14] reported that STK11/AMPK/TSC tumor suppressor axis can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin catalytic activity. The inhibition of mammalian target of rapamycin reduces the translation of mRNA molecules encoding oncogenic proteins, resulting in a strong antileukemic activity against primary AML cells. Christian Marinaccio found that loss of STK11 leads to stabilization of HIF1a and promotes the disease progression of the myeloproliferative neoplasms to AML, indicating that STK11 is a tumor suppressor in the myeloproliferative neoplasms [15]. By contrary, Yusuke Tarumoto reported that STK11 and its salt-inducible kinase effectors (SIK3) plays an essential role to maintain MEF2C function which is an essential transcription factor for the proliferation of leukemia cells [16]. Huihan Wang found that LKB1 downregulation can suppress the long-term proliferation of leukemia stem cells (LSCs), induce LSCs into G2/M phase, and enhance the sensitivity of LSCs to chemotherapy [17].

At present, there is no research or case report on the relationship between STK11/THBD and family aggregation of hematological malignancies. We report for the first time that an AML patient with STK11 and THBD mutations has a family aggregation of hematological malignancies, and consider that STK11 and THBD may be related to family genetic changes which ultimately cause the family aggregation of hematological malignancies. More clinical case studies and basic experiments are needed.

This study protocol was reviewed and the need for approval was waived by the Ethics Committee of People’s Liberation Army, the General Hospital of Western Theater Command. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The authors certify that they have obtained all appropriate patient consents. The patient knows that his name and initial will not be published, and the author will try to hide the patient’s identity, but anonymity cannot be guaranteed. The authors all agree to publication.

The authors declare no conflict of interest.

We gratefully acknowledge the financial support provided by the Natural Science Foundation of Sichuan Province (Grant No. 2022NSFSC1330 and 2021YJ0145); The incubation program of General Hospital of Western Theater command (Grant No. 2021-XZYG-C46) and The general program of General Hospital of Western Theater Command (Grant No.  2021-XZYG-B32).

N.Z. performed the clinical data. X.-J.M. performed clinical treatment. Y.-R.S. and F.-Y.F. performed the public dataset analysis. H.Y. and Y.-L.L. supervised the whole study and wrote the paper. The author(s) read and approved the final manuscript.

The data supporting the conclusions of this article are provided in this article. In addition, all data from this study can be obtained from the corresponding author upon reasonable request.