Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia

Flotho, Christian

doi:10.1080/15592294.2019.1583039

Cited by 6 publications

(5 citation statements)

References 77 publications

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“…The e cacy of the DNA methyltransferase inhibitor azacitidine as pre-transplant therapy has already been proven in several clinical trials with JMML patients but drug resistance still remains a major problem (30). Different mechanisms contribute to resistance to hypomethylating agents including deregulation of apoptotic pathways by changes of BCL-2 protein levels (31).…”

Section: Discussionmentioning

confidence: 99%

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

Erlacher

Zehnle

et al. 2023

Preprint

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Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce both leukemic burden and risk of relapse. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3-mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3-mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 but also promotes the differentiation of JMML cells towards mature myeloid cells. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.

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Section: Discussionmentioning

confidence: 99%

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

Erlacher

Zehnle

et al. 2023

Preprint

Self Cite

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show abstract

“…The efficacy of the DNA methyltransferase inhibitor azacitidine as pre-transplant therapy has already been proven in several clinical trials with JMML patients but drug resistance still remains a major problem [ 33 ]. Different mechanisms contribute to resistance to hypomethylating agents including deregulation of apoptotic pathways by changes of BCL-2 protein levels [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

Wu,

Zehnle,

Rajak

et al. 2023

Leukemia

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Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.

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“…A DNA methyltransferase-inhibiting azanucleoside is assumed to reverse the epigenetic dysregulation in malignant cells. This has led to a European protocol to employ DNA hypomethylating agents such as azacitidine for therapy in JMML [27]. The first case report of azacitidine for JMML before HSCT was published in 2009.…”

Section: Treatmentmentioning

confidence: 99%

Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of KMT2A-Rearranged Acute Myeloid Leukemia (AML)

Saad¹

2021

Acute Leukemias

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Juvenile myelomonocytic leukemia (JMML) is the most confusing mimicker of KMT2A-rearranged acute myeloid leukemia (AML). Clinical presentation, age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features. To complicate matters, JMML morphologically resemble acute myelomonocytic leukemia (AML M4) and distinction must be made based on accurate blast and promonocyte counts. As treatment significantly varies, AML/JMML overlap can lead to catastrophic consequences that can be avoided by timely management. Therefore, meticulous knowledge of JMML is essential to treat patients with hematologic malignancies. The pathognomic feature of JMML is increased infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of JMML. We can now molecularly confirm the diagnosis of JMML in approximately over 90% of patients who harbor driver mutations in KRAS, NRAS, PTPN11, NF1, or CBL genes. The presence of monosomy 7 is a classic feature of JMML that can support the diagnosis in many cases. On the other hand, cytogenetics and Fluorescence in situ hybridization analysis (FISH) are indispensable to differentiate KMT2A-rearranged AML from JMML. In particular, AML with t(9;11) is associated with monocytic features that can be easily mistaken for JMML.

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Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia

Cited by 6 publications

References 77 publications

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of KMT2A-Rearranged Acute Myeloid Leukemia (AML)

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