AML1–ETO meets JAK2: clinical evidence for the two hit model of leukemogenesis from a myeloproliferative syndrome progressing to acute myeloid leukemia

Schneider, Friederike; Bohlander, Stefan K.; Schneider, Stephanie; Papadaki, Christina; Kakadyia, P; Dufour, Annika; Vempati, Sridhar; Unterhalt, Michael; Feuring‐Buske, Michaela; Buske, Christian; Braess, Jan; Wandt, Hannes; Hiddemann, W.; Spiekermann, Karsten

doi:10.1038/sj.leu.2404830

Cited by 13 publications

(7 citation statements)

References 15 publications

(17 reference statements)

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“…More recently, coexistence of JAK2V617F and BCR-ABL has also been reported in chronic myeloproliferative disorders 19,20 and association of JAK2V617F with t(8;21) in AML therapy-related 21 or secondary to a myeloproliferative syndrome. 22 In conclusion, our data unequivocally confirm in a large series of patients with acute myeloid leukemia that NPM1 mutations are mutually exclusive of other recurrent genetic abnormalities and that NPM1 mutations identify a distinct acute myeloid leukemia genetic entity which should be considered for inclusion in the upcoming WHO Classification.…”

Section: Resultssupporting

confidence: 73%

NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

Falini¹,

Mecucci²,

Saglio³

et al. 2008

Haematologica

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Section: Resultssupporting

confidence: 73%

NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

Falini¹,

Mecucci²,

Saglio³

et al. 2008

Haematologica

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“…25, 26, 27, 28 This concept is supported by clinical evidence as well since multiple genetic hits are often diagnosed in AML patients. 21, 22, 23, 24 …”

Section: Discussionmentioning

confidence: 99%

“…This concept is supported by clinical evidence from a variety of leukemias, in which multiple genetic hits are often diagnosed in AML patients. 21, 22, 23, 24 Moreover, mouse transplantation models have shown that several genetic changes collaborate to induce AML. 25, 26, 27, 28 …”

Section: Introductionmentioning

confidence: 99%

High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event

et al. 2010

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Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline-inducible mouse model of AML, in which the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous, as ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10-induced overexpression. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. Interestingly, high levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia after removal of the primary event. This suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia.

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“…Two-hit model was proposed for Fig. 1 Bone marrow biopsy of the patient showed a markedly hypercellular marrow implying ALL the clonal evolution of leukemia [13]. Genome sequencing indicated that most mutations in the leukemia genome were random events and the acquirement of one or two initiating mutations generated the founding clone for leukemogenesis [14].…”

Section: Discussionmentioning

confidence: 99%

An unusual hematopoietic stem cell transplantation for donor acute lymphoblastic leukemia: a case report

Zhou¹,

Xie²,

Chen

et al. 2020

BMC Cancer

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Background: Donor acute lymphoblastic leukemia with recipient intact is a rare condition. We report a case of donor developing acute lymphoblastic leukemia 8 yrs after donating both bone marrow and peripheral blood hematopoietic stem cells. Case presentation: This case report describes a 51-year old female diagnosed with acute lymphoblastic leukemia who donated both bone marrow and peripheral blood stem cells 8 yrs ago for her brother with severe aplastic anemia. Whole exome sequencing revealed leukemic genetic lesions (SF3B1 and BRAF mutation) only appeared in the donor sister, not the recipient, and an unusual type of hematopoietic stem cell transplantation with the recipient's peripheral blood stem cells was done. The patient remained in remission for 3 months before disease relapsed. CD19 CART therapy followed by HLA-identical unrelated hematopoietic stem cell transplantation was applied and the patient remains in remission for 7 months till now. Conclusions: This donor leukemia report supports the hypothesis that genetic lesions happen randomly in leukemogenesis. SF3B1 combined with BRAF mutation might contribute to the development of acute lymphoblastic leukemia.

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AML1–ETO meets JAK2: clinical evidence for the two hit model of leukemogenesis from a myeloproliferative syndrome progressing to acute myeloid leukemia

Cited by 13 publications

References 15 publications

NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event

An unusual hematopoietic stem cell transplantation for donor acute lymphoblastic leukemia: a case report

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