Mar23 A1-Hematopoiesis and Leukemias Flashcards
(imp) myeloproliferative diseases charact. + the prototype one
- cancerous stem cell disorder of the BM
- increased cell number but intact differentiation
- may affect one or more cell lines
- may affect WBC, RBC or platelets
- may see prolif of other cells (fibroblasts for ex in myelofibrosis), in rarer entities
- prototype = CML, driven by the bcr-abl kinase
(imp) treatment idea of CML and consequence
- target bcr-abl
- this restores normal hematopoiesis
(imp) myelodysplastic diseases two types + risk with them (related to the two types)
- low and high risk disease
- may transform to AML (M for myelogenous, myelocytic, myeloblastic), related to low vs high risk
(imp) myelodysplastic diseases charact
- cancerous stem cell disorder of the BM
- increased cell number but impaired differentiation
- results in cytopenias (decrease in circulating cells)
(imp**) four major subtypes of MPNs (myeloproliferative neoplasms, disorders) AND main cell type affected in each
- chronic myeloid leukemia (CML): WBCs
- essential thrombocytosis: platelets
- polycythemia rubra vera (PRV): RBCs
- myelofibrosis: fibroblasts (accumulate in the BM)
(imp) CML: what happens and main thing
- translocation event in the HSC, abl (9) and bcr (22) fusion on philadelphia chromosome
- abl, kinase responsible for cell growth and division, is always active
- accumulation of uncontrolled GRANULOCYTES (are WBCs)
- differentiation is intact in early disease
(imp) causes or categories of MDS (myelodysplastic syndromes)
- primary or de novo (no clear cause, may be certain toxins)
- therapy-related MDS (secondary to chemo, radiation)
- related and secondary to hematologic disorders (aplastic anemia, MPNs, paroxysmal hemoglobinuria)
4 broad categories of leukemias
- acute lymphoblastic leukemia (ALL)
- acute myeloid leukemia (AML)
- chronic lymphocytic leukemia (CLL)
- chronic myeloid leukemia (CML)
(imp?) 3 main acute leukemias (def of acute leukemia = blast count over 20% in BM or blood)
- AML (acute myeloid leukemia)
- ALL (acute lymphoblastic leukemia)
- APL (acute promyelocytic leukemia (M3)) (a subtype of AML)
(imp?) most common acute leukemia in adults and its prognosis
AML. prognosis is variable and depends on cytogenetics
(imp?) how AML occurs + 2 most frequent initiating mutations
- stepwise accumulation of mutations by a HSC leading. (early, late and relapse specific mutations)
- clonal hematopoiesis leads to different clones with different mutations and deletions
- DNMT3 and NPM1
(imp?) most common acute leukemia in children and its prognosis
acute lymphoblastic leukemia (ALL)
- excellent prognosis in children, with multiagent chemo
- less good prognosis in adults
(imp?) acute promyelocytic leukemia M3 (APL) how it occurs
- often, translocation of chrom 15 and 17
- gives fusion protein of PML gene (chrom 15) and retinoic acid receptor alpha (chrom 17) driving disease
- RARa which normally binds RA in cytoplasm and then goes to nucleus as a TF doesn’t go in nucleus anymore = BLOCK IN DIFFERENTIATION
(imp?) APL treatment and prognosis
- good prognosis with all-trans-retinoic acid (noticed you can overcome the block with more retinoic acid)
- arsenic trioxide in relapsed disease
(imp?) 2 examples of leukemias where pathophysiology insights are useful for a targeted treatment decision
- bcr-abl fusion protein in CML. kinase inhibitors like imatinib
- PML-RARa fusion protein in APL. all-trans-retinoic acid
leukemia def and chronic vs acute
- myeloid or lymphoid cancer starting in the BM
- acute = aggressive
- chronic = more indolent
myeloid vs lymphoblastic or lymphocytic leukemia
myeloid = arises in stem cells giving rise to RBCs, megakaryocytes (megakaryocyte erythrocyte progenitor lineage) and granulocytes (macrophages, mast cells, etc.) (granulocyte myeloid progenitor lineage) lymphoid = in the lineage of the common lymphoid progenitor (gives B, T, NK)
chronic leukemia how present most commonly
elevated white count, abnormal CBC
2 chronic leukemias
- chronic myeloid leukemia (CML), is a MPN
- CLL (chronic lymphoid leukemia). subtype of B cell lymphoma, mature B lymphocytes expressing CD5 (atypical), a T cell marker. **remember CLL is SLL (small lymphocytic lymphoma: a low grade mature B cell NHL)’s leukemia counterpart
exact definition of an acute leukemia (myeloid or lymphoid)
having a blast count (count of blast cells) of over 20% in the BM or in the blood)
blast cell def
- earliest (most immature) distinguishable hematopoietic cell
- large size, large nucleus, ctly open DNA, prominent nucleolus
acute leukemia how present commonly
- pancytopenia
- constitutional symptoms (fever, fatigue, bone pain, malaise)
- tissue infiltration by blast cells
- coagulation disturbances
- leukostasis syndromes (accum of blasts in microcirculation with impaired perfusion. lungs and CNS affected)
- tumour lysis syndromes
how acute leukemia is diagnosed
BM study
good, intermediate and poor risk categories in AML (means if can control disease and prevent death with chemo)
good risk = CML, APL and chrom 16 transloc
intermediate risk = normal chromosomes or trisomy
poor risk = abnormal chrom 5 or 7, 11q23 (chrom 11) abnormality in MLL (mixed lineage leukemia), 3 or more chrom abnormalities
