Single-cell analysis based dissection of clonality in myelofibrosis

Mylonás, Elena; Yoshida, Kenichi; Frick, Mareike; Hoyer, Kaja; Christen, Friederike; Kaeda, Jaspal; Obenaus, Matthias; Noerenberg, Daniel; Hennch, Cornelius; Chan, Willy; Ochi, Yotaro; Shiraishi, Yuichi; Shiozawa, Yusuke; Zenz, Thorsten; Oakes, Christopher C.; Sawitzki, Birgit; Schwarz, Michaela; Bullinger, Lars; Coutre, Philipp le; Rose-Zerilli, Matthew; Ogawa, Seishi; Damm, Frédérik

doi:10.1038/s41467-019-13892-x

Cited by 57 publications

(59 citation statements)

References 62 publications

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“…To date, FLT3 mutations are a widely recognized AML-associated driver mutations. The FLT3-TKD mutation, carried by the patient, like the canonical FLT3-ITD, constitutively activates the receptor and promotes cell proliferation16 .Regarding the global mutational profile of single cells studied at the zygosity level, we observed a significant increase in the clonal heterogeneity during disease evolution, in agreement with recent data by Mylonas et al17 . This causes the expansion of highly mutated clones in later stages of the disease, accounting for the worsening of the patient' conditions.…”

supporting

confidence: 91%

Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Parenti

Rontauroli

Carretta

et al. 2020

Preprint

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Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decision, we studied single cell genomics and transcriptomics of CD34+ cells from a primary myelofibrosis (PMF) patient who progressed to acute myeloid Leukemia (AML) while receiving Ruxolitinib. Single cell genomics allowed the reconstruction of clonal hierarchy and demonstrated that TET2 was the first mutated gene while FLT3 was the last one. Disease evolution was accompanied by increased clonal heterogeneity and mutational rate, but clones carrying TP53 and FLT3 mutations were already present in chronic phase. Single cell transcriptomics unraveled repression of interferon signaling suggesting an immunosuppressive effect exerted by Ruxolitinib. Moreover, AML transformation was associated with a differentiative block and immune escape. These results suggest that single cell analysis can unmask tumor heterogeneity and provide meaningful insights about PMF progression that might guide personalized therapy.

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supporting

confidence: 91%

Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Parenti

Rontauroli

Carretta

et al. 2020

Preprint

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“… 28 , 29 Clonal evolution is not halted suggesting a rather limited disease-modifying potential. 30 , 31 …”

Section: Jak2 Inhibitors To Target Mpn Pathogenesismentioning

confidence: 99%

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Brkić

Meyer

2020

HemaSphere

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Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders with dysregulated myeloid blood cell production and propensity for transformation to acute myeloid leukemia, thrombosis, and bleeding. Acquired mutations in JAK2, MPL, and CALR converge on hyperactivation of Janus kinase 2 (JAK2) signaling as a central feature of MPN. Accordingly, JAK2 inhibitors have held promise for therapeutic targeting. After the JAK1/2 inhibitor ruxolitinib, similar JAK2 inhibitors as fedratinib are entering clinical use. While patients benefit with reduced splenomegaly and symptoms, disease-modifying effects on MPN clone size and clonal evolution are modest. Importantly, response to ruxolitinib may be lost upon treatment suggesting the MPN clone acquires resistance. Resistance mutations, as seen with other tyrosine kinase inhibitors, have not been described in MPN patients suggesting that functional processes reactivate JAK2 signaling. Compensatory signaling, which bypasses JAK2 inhibition, and other processes contribute to intrinsic resistance of MPN cells restricting efficacy of JAK2 inhibition overall. Combinations of JAK2 inhibition with pegylated interferon-α, a well-established therapy of MPN, B-cell lymphoma 2 inhibition, and others are in clinical development with the potential to enhance therapeutic efficacy. Novel single-agent approaches targeting other molecules than JAK2 are being investigated clinically. Special focus should be placed on myelofibrosis patients with anemia and thrombocytopenia, a delicate patient population at high need for options. The extending range of new treatment approaches will increase the therapeutic options for MPN patients. This calls for concomitant improvement of our insight into MPN biology to inform tailored therapeutic strategies for individual MPN patients.

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“…Clonal dynamics play a role as well, with higher JAK2 mutant allele fractions and lower number of mutations predicting favorable responses [ 22 , 23 ]. In addition, RAS pathway mutations have recently been associated with resistance to JAK inhibitors and poor outcomes [ 24 , 25 , 26 ]. Durability of spleen response to ruxolitinib treatment is associated with improved overall survival, while thrombocytopenia and clonal evolution correlate with inferior outcomes [ 27 , 28 ].…”

Section: Rationale For Combination Therapymentioning

confidence: 99%

“…Other combinations that are supported by preclinical data and have yet to reach, or just recently entered, clinical testing are worth noting. Recent reports have suggested that disease progression in MF patients treated with ruxolitinib is associated with activation of receptor tyrosine kinase and RAS pathway mutations, and RAS pathway mutations, including PTPN11 (which encodes the SHP2 phosphatase), confer poor prognosis [ 24 , 25 ]. Notably, inhibition of MEK, a mediator of MAP kinase signaling, has been shown to be effective in murine models as a single agent as well as in combination with ruxolitinib [ 175 ].…”

Section: Novel Combinations Pending Clinical Experiencementioning

confidence: 99%

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

Kuykendall

Horvat

Pandey

et al. 2020

Cancers

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Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest.

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Single-cell analysis based dissection of clonality in myelofibrosis

Cited by 57 publications

References 62 publications

Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

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